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Arboviruses JOHN T ROEHRIG AND ROBERT S LANCIOTTI 23 LABORATORY PROCEDURES FOR DETECTING VIRUSES Introduction The term arbovirus is a contraction of “arthropod-borne virus” and has no phylogenetic or classification significance This term describes the mechanism by which these viruses are transmitted and maintained in nature: through the bite of a hematophagous arthropod Most medically important arboviruses are transmitted by either mosquitoes or ticks In the United States alone, representatives from at least five virus families can be transmitted by biting arthropods (Table 1) This review will focus on the medically important arboviruses Because these viruses are transmitted by arthropods, arboviral disease usually manifests itself during the warmer months in the temperate climates of the world Arboviral disease can, however, be contracted in the winter months in milder climates, and disease transmission can occur year round in the tropics During the milder times of the year, or depending on the patient’s travel history, testing for arboviruses should be included in the laboratory diagnosis of cases compatible with arboviral infections There are 535 arboviruses listed in the International Catalogue of Arboviruses (Karabatsos, 1985), but most have not been associated with human disease Continued encroachment on the world’s tropical rainforests, however, coupled with rapid transport of humans and animals, makes arboviruses emerging and reemerging pathogens This observation means that new arboviruses may be associated with human diseases or known arboviruses may cause outbreaks in previous or new locales The discovery of West Nile (WN) virus (WNV) in the United States in 1999 is a recent example of arbovirus movement Identification of emerging agents will, by definition, be difficult, with the medical and veterinary community depending on specialty reference laboratories capable of working with and identifying these biosafety level and pathogens (Centers for Disease Control and Prevention, 1993) The World Health Organization (WHO) sponsors a laboratory network of WHO Collaborating Centers distributed throughout the world, which specialize in diagnosing arboviral diseases It is likely that a clinical sample from an arbovirus infection will end up at one of these laboratories for diagnosis or confirmation d e t i n U G R V History Yellow fever (YF) epidemics probably occurred as early as 1648 in the Yucatan Peninsula of Mexico Aedes aegypti mosquitoes, which are the urban vectors of YF, also transmit dengue (DEN) virus, the cause of DEN fever DEN fever outbreaks occurred quite frequently in the southern United States until the 1920s, when populations of the vector mosquito were controlled Both DEN and YF continue to occur in tropical America and Africa, even though an effective YF vaccine exists This inability to control YF despite the availability of an effective vaccine reflects the poor economic conditions of the countries where YF is endemic, where this vaccine is still too expensive for general use (Monath, 1991) DEN virus also causes DEN hemorrhagic fever (DHF) and DEN shock syndrome (DSS), which currently occur as major, lethal epidemics of children in Southeast Asia and appeared for the first time in the New World in Cuba in 1981 (Kouri et al., 1983; Guzman et al., 1984; Guzman et al., 1990) The primary clinical manifestation of life-threatening arboviral disease in North America has been encephalitis Three mosquito-borne viruses that cause human encephalitis were discovered during the 1930s Western equine encephalitis (WEE) virus was isolated in 1930 from horses (Meyer et al., 1931) and in 1938 was associated with encephalitis in humans in California It now occurs infrequently in the irrigated farmland of the western United States and Canada Eastern equine encephalitis (EEE) was isolated in 1933 from horses (TenBroeck and Merrill, 1933) It was subsequently isolated from people in 1938 Currently, EEE has a distribution throughout most of the eastern half of the United States The first outbreak of St Louis encephalitis (SLE) virus occurred in 1933 in St Louis, MO, with 1,095 reported cases (Cumming, 1935) The last major SLE epidemic was in 1975, with 1,815 reported cases Endemic (rural) SLE may occur each year in much of the western United States (Monath and Tsai, 1987; Tsai et al., 1987b; Reisen et al., 1990; Reisen et al., 1992a; Reisen et al., 1992b; Reisen and Chiles, 1997) It has been hypothesized that major urban SLE outbreaks occur every to 10 years; however, this no longer appears to be the case The reduction in the incidence of SLE may be due to human lifestyle modifications, such as the use of air conditioning and television Focal outbreaks can occur each year; however, many times they are localized to the poorer 387 vip.persianss.ir 388 VIRAL PATHOGENS TABLE Medically important arboviruses in the United States Virus family Togaviridae Flaviviridae Bunyaviridae Reoviridae Rhabdoviridae Pathogen EEE virus WEE virus VEE virus WNV SLE virus POW virus DEN virus CAL serogroup viruses LAC encephalitis virus CAL encephalitis (CE) SSH virus JC virus CV virus CTF virus VSV Related virus(es) HJ virus SLE virus WNV Many None Rabies virus urban areas in scattered locations such as Chicago, Philadelphia, Houston, and New Orleans Two other encephalitis viruses, WNV and Venezuelan equine encephalitis (VEE) virus, have been associated with major epidemics or are maintained in nature in enzootic cycles The varieties of VEE viruses associated with these differing epidemiologic presentations can be separated both serologically and through genetic analysis VEE virus has caused major human epidemics periodically throughout Central and South America since the 1930s, the most recent in 1995 in Colombia and Venezuela (Kinney et al., 1989; Sneider et al., 1993; Weaver et al., 1996; Rivas et al., 1997; Kinney et al., 1998) It is now believed that the earliest VEE epidemics were caused by incompletely inactivated vaccines (Sneider et al., 1993; Weaver et al., 1999) Current VEE epidemics are caused by epidemic strains of VEE virus thought to have evolved from naturally occurring enzootic VEE viruses (Rico-Hesse et al., 1995; Powers et al., 1997; Kinney et al., 1998) The reasoning for this is derived partly from the inability to isolate epidemic VEE viruses during interepidemic periods Following the discovery of WNV in the New York City area in 1999, it has now become the leading cause of vectorborne human encephalitis in the United States WNV has spread throughout the continental United States and Canada, and there is serological evidence for WNV activity in Mexico, Central and South America, and the Caribbean It is of interest that a variety of novel modes of transmission of WNV have been either suggested or proven (Iwamoto et al., 2003; Avalos-Bock, 2005; Busch et al., 2005; Hoekstra, 2005; Kusne and Smilack, 2005; Kuehn, 2006; Lee and Biggerstaff, 2006; Montgomery et al., 2006; O’Leary et al., 2006; Hinckley et al., 2007) These modes include blood, transplanted tissue, and human breast milk (transmission to infants through the milk of infected mothers) Detailed reviews for all of these viruses as well as a currently emerging encephalitis caused by the California (CAL) serogroup virus, La Crosse (LAC) encephalitis, are recommended for further study (Calisher and Thompson, 1983; Monath, 1988, 1996; Trent et al., 1989; Tsai and Monath, 1996: McJunkin et al., 1998) General Considerations Laboratory diagnosis of arboviral infections has traditionally been based upon serological identification of antiviral antibodies and/or isolation of virus While the classical serological assays of hemagglutination inhibition (HI), complement fixation (CF), and neutralization (NT) of virus infectivity have been replaced by enzyme-linked immunosorbent assay (ELISA), each of these earlier tests still have applicability The timing after infection of certain viral infections can sometimes be ascertained with the CF test While the laboratorian can readily distinguish between virus families (e.g., flaviviruses and togaviruses), within an individual family, many of the viruses are so closely related antigenically that only the virus NT test can differentiate infections While the expensive technique of virus isolation by inoculation into susceptible cell culture is losing ground to more rapid assays like PCR and antigen-detection ELISA, the former approach is still useful For example, alphaviruses replicate in common continuous cell cultures like Vero or BHK-21 cells, often demonstrating virus-specific cytopathic effects within 24 hours These virus-infected cells can then be used to identify the infecting agent by indirect immunofluorescence assay (IFA) using well-characterized virus-specific murine monoclonal antibodies (MAbs) Very few PCR assays developed for arboviruses have been critically and completely analyzed to the extent that they now function as simple and reproducible lab tests The caveat with all newer assays that detect only viral protein or nucleic acid is their inability to produce replicating virus useable for future serologic or genetic analysis G R V d e t i n U Methods Used Basic Principles A historical analysis of arboviral infections investigated at the WHO Collaborating Centers for arboviruses in the Division of Vector-Borne Infectious Diseases, U.S Centers for Disease Control and Prevention (CDC), identified the viruses that cause enough disease to warrant their inclusion in routine diagnostic virology testing panels These panels include representatives from all virus families and can be organized by their geographic distribution The decision of which virus panel is used can be based upon the patient’s location and travel history (Fig 1) These viruses are not the only arboviral agents responsible for disease; but rather, these virus panels should detect the majority of arboviral infections Regardless of the assay employed, confirmation of arboviral infection requires acute- and convalescent-phase serum samples that yield a demonstrable increase in antiviral antibody activity Introduction of ELISA protocols that measure virus-specific immunoglobulin M (IgM), especially when applied to acute-phase serum or cerebrospinal fluid (CSF) samples, yield good approximations of recent infections when the timing after infection of the specimen is appropriate For some arboviruses, however, IgM reactivity can be measured weeks after the onset of disease For most arboviruses, serologic cross-reactivity with related viruses increases as the infection progresses Because of this and the close antigenic relatedness of many of the agents within the same virus family, IgG ELISAs are often not very specific Regardless of this, it is a simple matter to differentiate viruses from different families (e.g., togaviruses from flaviviruses) Because epitopes that elicit virus-neutralizing antibody are under the most severe immunologic pressure, these epitopes are usually the most virus specific Consequently, the virus NT assay demonstrates a fair amount of serologic specificity, even with convalescent-phase serum samples vip.persianss.ir 23 Arboviruses 389 G R V d e FIGURE Antigen panels for arboviral testing based upon geographic distribution and prevalence Abbreviations: EVE, Everglades VEE; SF, Semliki Forest; SIN, Sindbis; TAH, Tahyna; INK, Inkoo; RVF, Rift Valley fever; ORO, Oropouche; KUN, Kunjin t i n Applications Serology for Antibody Testing HI The HI test measures the ability of antiviral antibody to block the virus capacity to agglutinate erythrocytes (Clarke and Casals, 1958) This was the first technique used to characterize arboviruses The HI test successfully differentiated togaviruses (group A arboviruses, primarily alphaviruses) from flaviviruses (group B arboviruses) long before modern biochemical techniques confirmed this observation Many laboratories still utilize the HI test, although with the advent of ELISA, it is being replaced The HI test requires preparation of tedious hemagglutination buffers, continual test standardization, and the routine availability of gander erythrocytes As the disease progresses, virus cross-reactivity in the HI test also increases It is not uncommon for convalescent-phase serum samples to react with two or more virus antigens within the same virus family, making even a fourfold or higher serum HI titer rise between acute- and convalescent-phase serum samples difficult to interpret U CF The CF test measures the ability of the antiviral antibody to fix complement in the presence of virus antigen Quite possibly, it is more difficult to maintain proper quality control of the CF test than the HI test Consequently, it is used in only special situations, such as attempting to determine the timing after infection of an individual serum sample (Monath et al., 1980) Because CF antibody appears later in infection but has a shorter half-life (around years), this test has been used as an indicator of more recent primary infection With the advent of the IgM ELISA, allowing for direct measurement of the early IgM antibody, CF tests are not as useful The CF test may, however, indicate a recent infection if the serum sample is taken after the IgM antibody has waned PRNT The plaque-reduction neutralization test (PRNT) is a contradiction among assays used to diagnose arboviral infection It is by far the most expensive and problematic test to perform, but it is still the only serologic assay able to reliably differentiate infection between two closely antigenically related viruses The subtlety of the PRNT is based upon the plaquing requirements of various arboviruses Plaquing of arboviruses is usually performed in a variety of continuous mammalian cell lines The most common of these are Vero, BHK-21, and CER cells Both plaque size and morphology might differ, depending on the cell type used Time to plaque formation also varies Flaviviruses may take to 10 days for plaques to form, while alphaviruses usually plaque in 24 to 48 h To perform the PRNT, a virus seed of known titer must be available Since many arboviruses lose titer upon freezethawing, it is best to have multiple aliquots of the virus seed A constant amount of virus (50 to 100 PFU) is mixed individually with dilutions of the serum being tested Following plating on cells, plaques are visualized by adding a solution of the vital dye neutral red The number of plaques in an individual plate is then divided by the starting number of virions to calculate a percent neutralization Typically, the PRNT is interpreted at a 70% PRNT titer, that is, the last dilution of serum that inhibits 70% of the total added plaques vip.persianss.ir 390 VIRAL PATHOGENS MAC-ELISA Currently, the ELISA is used to measure either IgM or IgG individually As with other infections, IgM titers usually signify recent virus infection While many IgM protocols have been designed over the years, the most appropriate protocol for measuring IgM is the IgM-capture ELISA (MAC-ELISA) (Westaway et al., 1974; Heinz et al., 1981; Burke and Nisalak, 1982; Jamnback et al., 1982; Monath et al., 1984; Bundo and Igarashi, 1985; Burke et al., 1985a; Burke et al., 1985b; Calisher et al., 1985a; Calisher et al., 1985c; Carter et al., 1985; Dykers et al., 1985; Calisher et al., 1986a; Calisher et al., 1986b; Calisher et al., 1986c; Besselaar et al., 1989; Cardosa et al., 1992; Sahu et al., 1994; Kittigul et al., 1998; Martin et al., 2002; Martin et al., 2004) This approach minimizes the interference of the higher-avidity IgG with IgM binding to antigen and consequently is more sensitive than the indirect ELISA format for IgM (Heinz et al., 1981) The capture design also permits use of antigen from a variety of sources, including those that normally have too much irrelevant protein for direct coating of plates In the MACELISA, human antiviral antibody is first captured into a 96-well ELISA plate by precoated commercial anti-human IgM antibody The virus specificity of this captured IgM is determined by reacting individual wells with different virus antigens The captured virus antigen is then detected with an antiviral antibody The most efficient MAC-ELISA design uses broadly crossreactive murine MAbs, conjugated to enzyme as antiviral antigen detector molecules Three of these MAbs—2A2C-3 (broad alphavirus reactor), 6B6C-1 (broad flavivirus reactor), and 10G-4 (broad bunyavirus reactor)—are currently used to identify viral antigens from these three virus families (Table 2) (Roehrig et al., 1983; Roehrig et al., 1990a; Ludwig et al., 1991) Since the absorbance recorded in this ELISA is dependent upon the amount of antiviral antibody in the sample (provided that antigen is in excess), this ELISA can be run first at a single screening dilution (e.g., 1:400) The results from the MAC-ELISA are usually interpreted by dividing the absorbance of the test sample on antigen (P) by the absorbance of a negative control serum on antigen (N) In our laboratory, P/N ratios of ≥2.0 are considered positive, with the caveat that P/N values between and are often false positives In this case, another serological assay (e.g., PRNT) should be performed to confirm equivocal results Alternatively, a convalescent-phase serum can be tested The antibody titer in this specimen should have increased from that of the acute-phase specimen The MAC-ELISA is capable of distinguishing among infections caused by the medically important alphaviruses (EEE, WEE, and VEE) Commercial IgM enzyme immunoassay kits are now being produced There are currently U.S Food and Drug Administration-approved and commercially available MAC-ELISAs to detect WNV infection The microplatebased MAC-ELISA has been adapted to lateral-flow tests in dipstick or cassette format This makes the test qualitative rather than quantitative but permits rapid field testing of specimens (Sathish et al., 2002; Prince et al., 2005; Niedrig et al., 2007; Rawlins et al., 2007; Sambol et al., 2007) Blocking ELISA With the discovery of WNV in the United States and the subsequent identification of a wide range of virus-infected animals, a new test was designed that did not rely on speciesspecific antibodies for performance This blocking ELISA is based upon the ability of infection immune sera to block the binding of reporter virus-specific MAbs to virus antigen (Blitvich et al., 2003a; Blitvich et al., 2003b; Jozan et al., 2003) A similar test had been developed previously for the Australian flavivirus, Murray Valley encephalitis (MVE) virus (Hawkes et al., 1990) The blocking ELISA has been used successfully with avian and equine sera; however, it has not been as useful for human serum samples for an as yet undefined reason G R V d e t i n U an indirect IgG ELISA has been developed in which virus antigen is captured into wells with broadly cross-reactive murine MAbs for each of the virus families (Table 2) (Johnson et al., 2000) These MAbs are first coated to wells, and then the appropriate viral antigen is added After virus antigen has been captured, this IgG functions like any other indirect ELISA Immune serum samples from infected individuals (infection immune) are added, and the binding of antiviral antibody is detected with a commercial anti-species antibody conjugated to enzyme While antigen is typically prepared as virus-infected mouse brain that has been processed to remove nonspecific inhibitors, virus-infected cell culture fluids also can be used The latter antigen is typically lower in activity There are commercial enzyme immunoassay kits available; however, their reliability has yet to be conclusively proven IgG ELISA Standard indirect IgG ELISA can be used with arboviruses (Frazier and Shope, 1979; Roehrig, 1982) The problem with this approach is the wide variety of agents causing these diseases It is simply too difficult and time-consuming to prepare pure virus antigen for even the limited subset of arboviruses used in antigen panels To circumvent this problem, Microsphere Immunoassay The MAC-ELISA and IgG ELISA for some arboviruses have been adapted to microsphere immunoassay (e.g., Luminex) This rapid flowthrough assay design is based upon microparticles containing mixtures of chromophores The wide range of chromophore mixtures available allows this approach to be multiplexed with more than one antigen For now, this approach has been applied to the flaviviruses WNV and SLE virus and is based upon the reactivity of antibodies with either the envelope (E) glycoprotein or the NS5 nonstructural protein (Wong et al., 2004; Johnson et al., 2005) Eventually, additional viruses will be added to the antigen cocktail, which should permit testing for a wide variety of viruses using only a single serum specimen IFA Test One of the oldest commercial assays for antibody to SLE, WEE, EEE, and LAC viruses is based upon end point titration of sera by IFA This kit is used by many public health and commercial labs Since this is an indirect format, the problems of IgG competition for IgM binding occur in the IgM IFA test The IFA test lacks both the sensitivity and quantitative characteristics of the ELISA For this reason, serological diagnosis based upon IFA titrations is not preferable Virus Isolation and Identification Three approaches are currently used to identify virus in complex solutions The oldest method is to inoculate specimens into susceptible cell cultures, wait for virus-specific cytopathic effects, and then identify the virus isolate by a complex serologic testing scheme More recent techniques use antiviral antibody to “capture” virus antigen from a solution to be later identified with antiviral antibody While both of these assays rely on viral proteins for the identification process, vip.persianss.ir 23 Arboviruses 391 TABLE MAbs useful in arbovirus identification Utility fora: Virus MAb Alphaviruses VEE virus 1A2B-10 5B4D-6 1A3A-5 1A4D-1 1A1B-9 1A3A-9 1A3B-7 WEE virus 2B1C-6 2A3D-5 2D4-1 2A2C-3 EEE virus 1B5C-3 1B1C-4 1A4B-6 Flaviviruses SLE virus 6B5A-2 4A4C-4 6B6C-1 JE virus JE314H52 6B4A-10 6A4D-1 MVE virus 4B6C-2 YF virus 5E3 2D12 864 117 DEN virus D2-1F1-3 3H5-1-21 D6-8A1-12 1H10-6-7 4G2 Bunyaviruses LAC virus 807-18 10G4 Virus specificity ELISA Ag captured IFA IHCb Referencec MAC IgG Wild-type VEE TC-83 VEE 1AB, 1C, 1AB, 1C, 1D 1D, 1E, 1F All subtype All VEE complex – – – – – – – – – – – – – – D D D D D D D + + + + + + + + + + + + + + Roehrig et al., 1991 Roehrig et al., 1982 Roehrig and Mathews, 1985 Roehrig and Mathews, 1985 Rico-Hesse et al., 1988 Roehrig and Mathews, 1985 Roehrig and Mathews, 1985 WEE WEE complex HJ All alphaviruses – – – + – – – – D C D D + + + + + + + + Hunt and Roehrig, 1985 Hunt and Roehrig, 1985 Karabatsos et al., 1988 Karabatsos et al., 1988 NA EEEe EEE complex All alphaviruses – – – – – + D D C + + + + + + Roehrig et al., 1990a Roehrig et al., 1990a Roehrig et al., 1990a SLE SLE All flaviviruses – – + – – – + + + + + + Roehrig et al., 1983 Roehrig et al., 1983 Roehrig et al., 1983 + + + + + + Unpublished Guirakhoo et al., 1992 Guirakhoo et al., 1992 D + + Hawkes et al., 1988 D D D D + + + + + + + + Schlesinger et al., 1983 Schlesinger et al., 1983 Gould et al., 1985 Gould et al., 1989 MVE YF YF Vaccine YF Wild-type YF U DEN1 DEN2 DEN3 DEN4 All flaviviruses LAC CAL group d e t i n JE JE complex JE, MVE G R V D C D – – – – – – D C D – – – – – – – – – – – – – – – – – – – + D D D D C + + + + + + + + + + Unpublished Henchal et al., 1985 Unpublished Henchal et al., 1982 Henchal et al., 1982 – + – + D C/D + + + + Gonzalez-Scarano et al., 1982 Ludwig et al., 1991 a +, useful; –, not useful IHC, immunohistochemistry Reference in which MAb was first described Publication lists all important biological characteristics of MAb d Used as capture (C) or detector (D) antibodies Ag, antigen e North American (NA) EEE viruses only b c vip.persianss.ir 392 VIRAL PATHOGENS the advent of PCR assays has now established genome identification as one of the primary tests for virus identification The evolution of rapid genome sequencing and the accumulation of large numbers of virus gene sequences have allowed PCR identification to evolve into a precise virus identification procedure For those labs that not have PCR capability, the development of virus-specific MAbs has improved the classic techniques of virus isolation and serologic identification to the extent that these approaches are still viable options for the clinical virology laboratory IFA Identification Previously, virus NT assays were necessary to differentiate closely related viruses such as flaviviruses There now exist MAb reagents capable of identifying a specific virus by IFA (Table 2) (Roehrig, 1986, 1990; Heinz and Roehrig, 1990; Roehrig and Bolin, 1997) There are also MAbs capable of identifying virus complexes and even larger virus groups (e.g., all alphaviruses or all flaviviruses) While these MAbs have replaced virus-grouping antisera prepared by the National Institutes of Health (NIH), the NIH grouping serum samples are still quite useful in characterizing those arboviruses for which few MAbs are available (e.g., bunyaviruses) Because of the short supply of the NIH grouping sera, these reagents are usually available to reference laboratories, whereas the MAb reagents are available to all public health laboratories and can identify all domestic medically important arboviruses Antigen-Capture ELISA Because of the high avidity and precise specificity of MAbs, these reagents are currently being fashioned into antigencapture ELISA protocols (Hildreth et al., 1982; Beaty et al., 1983; Hildreth and Beaty, 1983; Hildreth et al., 1984; Kuno et al., 1985; Monath et al., 1986; Scott and Olson, 1986; Tsai et al., 1987a; Tsai et al., 1988; Gajanana et al., 1995; Brown et al., 1996; Hunt et al., 2002) In these assays, viral proteins are immobilized onto a solid phase by an antiviral MAb This captured antigen is then detected by using an antiviral antibody conjugated to enzyme For simplicity, the detecting MAbs are usually broadly cross-reactive, such as the flavivirus MAb 6B6C-1 This approach reduces the number of enzyme conjugates necessary for virus identification These protocols are currently formulated in ELISA format, but some have been redesigned for commercial use as dipstick or lateral-flow assays (Ryan et al., 2003) The dipstick assays have been particularly useful in mosquito surveillance efforts, where smaller number of specimens are routinely tested, and the test is more amenable to field analyses Currently, antigencapture ELISA has been developed for EEE, WEE, SLE, LAC, WN, and DEN viruses While there have been no protocols published for VEE antigen detection, the MAbs are available, and development of this assay should not be far off MAbs useful in antigen-capture ELISA, as either capture or detector antibodies, are included in Table G R V RT-PCR Standard RT-PCR-based assays (compared to real-time assays described below) to detect arbovirus genomic sequences have been developed for a number of agents These assays use either virus-specific primers or consensus primers that are designed to amplify genetically related viruses Obtaining a DNA fragment of the predicted size is considered by some to be diagnostic Greater specificity can be achieved by using sequence-specific approaches for detecting and confirming the identity of the amplified DNA, including hybridization with virus-specific probes (i.e., Southern blot, dot blot, or microtiter plate hybridization), PCR amplification with additional primers internal to the original primers (nested or semi-nested PCR), restriction endonuclease digestion of the DNA product, or nucleic acid sequence analysis When consensus primers are utilized, a sequence-specific detection method, such as one of those described above, must be employed to specifically identify the resulting DNA, since by the design of the assay, related viruses would all be amplified Consensus RT-PCR assays have been described for alphaviruses, flaviviruses, and the CAL and Bunyamwera serogroup bunyaviruses (Pfeffer et al., 1997; Kuno, 1998; Lanciotti et al., 1999; Scaramozzino et al., 2001) Virus-specific assays include those for the DEN, YF, Japanese encephalitis (JE), WEE, EEE, SLE, MVE, Powassan (POW), tick-borne encephalitis (TBE), WN, CAL serogroup, Ross River (RR), Ockelbo, and Colorado tick fever (CTF) viruses d e t i n U of virus in serum using NAAT at the time of clinical presentation is typically unproductive, and a negative result is not informative Detection of virus in CSF obtained from meningitis or encephalitis patients is often better, with WNV being detected using a real-time reverse transcriptase PCR (RT-PCR) in 14% of acute-phase serum specimens and 57% of CSF specimens (Lanciotti et al., 2000) For nonencephalitic viruses (e.g., DEN viruses) often a much higher viremia with longer duration is achieved, resulting in detectable virus using isolation or NAAT methods In general, the alphaviruses demonstrate replication kinetics similar to those of the flaviviruses and are not commonly detected in acute-phase serum and/or CSF specimens, although detection is generally greater than with the flaviviruses In contrast, NAATs have been highly successful in detecting arboviruses from tissues obtained from fatal human cases when the appropriate tissue target is known and assayed (i.e., brain tissue in WNV, LAC, or EEE cases, liver tissue from YF cases, etc.) NAAT A variety of nucleic acid amplification test (NAAT) platforms have been successfully utilized for the detection of arboviruses In general, the sensitivity of any of the NAATs in identifying arboviruses has been shown to be equal to or greater than the most sensitive viral isolation or antigen detection procedures, while providing equal test specificity The dynamics of in vivo viral replication and tissue tropisms must be carefully considered so that the utility of a NAAT to a particular arbovirus can be properly applied and interpreted For example, with encephalitis viruses, the detection Real-Time 5¢ Exonuclease Fluorogenic Assays (TaqMan) TaqMan RT-PCR assays combine RT-PCR amplification with fluorescent-labeled virus-specific probes able to detect amplified DNA during the amplification reaction These assays offer numerous advantages over standard RT-PCR, namely, they are quantitative, high throughput, and rapid and have increased sensitivity and specificity The increased specificity of the TaqMan assay compared to standard RTPCR is due to the use of the virus-specific internal probe during the amplification Since postamplification characterization of the amplified DNA is not needed, amplified DNA is not manipulated in the laboratory, resulting in a reduced likelihood of amplicon contamination Real-time fluorogenic assays also offer the advantage of the ability to detect multiple targets at the same time in the same amplification reaction (multiplexing) Several TaqMan assays for the detection of arboviruses have been described, including those for WN, vip.persianss.ir 23 Arboviruses SLE, TBE, DEN, EEE, WEE, and LAC viruses (Lanciotti et al., 1992; Kuno et al., 1996; Lanciotti and Kerst, 2001) NASBA Another amplification technology which has been used successfully for the detection and identification of arboviruses is nucleic acid sequence-based amplification (NASBA) This approach shares some similarities with RT-PCR at the initial stages; however, there are several significant differences For NASBA, amplified RNA (not DNA) is detected in a sequence-specific manner NASBA has been successfully employed for the detection of a number of arboviruses, including WN, SLE, EEE, WEE, LAC, and DEN viruses (Lanciotti and Kerst, 2001) Advantages and Disadvantages and Tips Incorporation of MAb reagents into both serological assays and virus identification procedures has led to a new level of test standardization between diagnostic laboratories (Roehrig et al., 1998b) These readily reproducible and highly defined reagents continue to improve the rapidity, sensitivity, and specificity of all diagnostic procedures Similarly, the exquisite sensitivity of the PCR has created a paradigm shift in how infectious agents are handled and identified Highcontainment viruses can be handled safely after they have been subjected to nucleic acid extraction techniques Since the enhanced sensitivity of the PCR may lead to false-positive results, a diagnosis should not be based solely on a positive PCR result but should be confirmed with a diagnostic serologic assay Even though PCR and antigen-detection ELISA are rapid and sensitive techniques, it is still useful to actually isolate a virus Without having a virus in hand, future analyses will be impossible While the sensitivity of the newer assays can be spectacular, false positives can still occur In the MAC-ELISA, the majority of equivocal results occur when P/N ratios are between 2.0 and 3.0 In these instances, it is still necessary to confirm these results by an alternative serologic assay In the antigen-capture ELISA, the inhibition control is often not run, making the capture results uninterpretable (Roehrig et al., 1998b) Similarly, the classical approach of having paired serum samples is also still useful Even though MACELISA appears to be an excellent way to determine current infections, many times serum samples are taken so early after onset that even the IgM antibody titer is not yet measurable Both IgM and IgG antibodies will usually be found in convalescent-phase serum samples of these individuals (Roehrig et al., 1998b) Finally, the best approach to identifying and limiting arbovirus outbreaks is through good disease surveillance This surveillance may involve sampling of the mosquito vectors or sampling animal reservoirs Whichever approach is taken, since arboviral diseases know no political boundaries, communication of arboviral activities to agencies like CDC is imperative to formulate a national strategy for disease intervention CDC is also available to confirm laboratory testing for all labs that have possible arbovirus activity, especially those who have little experience with these diseases and, therefore, utilize commercial laboratories for their arboviral testing It must be remembered that there is no national certification process for these commercial laboratories, and consequently, some results may not be completely accurate the virus specificity of an antiflaviviral antibody response would be quite useful Even though sequence analysis can identify many unique regions among and between flaviviruses, the conformational dependence of many flavivirus epitopes dictates that sophisticated modeling and structurefunction analysis will be needed before these new antigens can be made New MAbs capable of identifying many arboviruses (especially the medically important bunyaviruses) are also needed Better and more rigorous testing of new PCR assays is necessary before they can be used routinely in the diagnostic laboratory Standardization of diagnostic techniques would greatly improve lab-to-lab reproducibility As new assays are developed, the pharmaceutical industry must take the lead in commercializing these tests and ensuring their validity With the exception of human immunodeficiency virus, arboviral infections can be considered the most important emerging or reemerging viral diseases There are three reasons for this First, as the world’s population continues to grow, humans will continue to encroach on the habitat of these zoonotic viral infections This encroachment, usually by nonimmune individuals, will result in epidemics of completely new viral diseases or the reemergence of quiescent diseases Second, as new agents are introduced into the human population, their ability to expand to new areas is facilitated by rapid transportation An individual infected with DEN virus in Southeast Asia can be back in the United States before symptoms occur These events could lead to new epidemics in completely new areas, where both physicians and laboratory personnel are unfamiliar with symptoms, diagnosis, and control measures Finally, there are very few approaches to prevention of these diseases, since neither vaccines nor therapeutic pharmaceuticals exist With this in mind, the physician and the diagnostic virology laboratory must consider arboviral diseases whenever symptoms, timing, exposure to insects, or travel history indicate possible arboviral infections G R V d e it n U 393 Future and Conclusions There is a continuing need for improvement in laboratory testing for arboviruses A serologic binding assay to identify VIRAL PATHOGENS Introduction While there are a few exceptions that will be noted later, arboviruses are usually associated with two major disease syndromes—encephalitis or hemorrhagic fevers Case incidence can vary from hundreds of thousands, as is the case with DEN virus, to a handful, as is the case for the ticktransmitted POW virus, which has caused only 21 reported cases of human encephalitis in the United States and Canada since it was first isolated in 1958 The severity of symptoms of arboviral infections can also vary Most cases of arboviral encephalitis are subclinical; however, infection with EEE can result in death or severe lifelong neurological deficits The continental United States has no indigenous arboviruses that cause hemorrhagic fever; however, travelers are at reasonable risk from infection with YF and DEN viruses Fortunately for the physician, many of the arboviral infections are caused by closely related viruses, so their ecology, entomology, and epidemiology are very similar, regardless of the continent on which the exposure occurred For example, the recent outbreak of WN encephalitis in Bucharest, Romania, had many features in common with urban outbreaks of SLE in the United States (Tsai et al., 1998; Han et al., 1999) A summary of the biochemical characteristics of the major families of arboviruses is shown in Table vip.persianss.ir 394 VIRAL PATHOGENS TABLE Characteristics of the families of common arbovirusesa Characteristic Size (nm) Morphology NA Polarity of NA Enveloped Structural proteins Nucleocapsid symmetry No of nucleocapsids RNA polymerase a Result for virus family: Togaviridae Flaviviridae 60–70 Spherical ssRNA Positive Yes E1, E2, C Icosahedral No 40–60 Spherical ssRNA Positive Yes E, C, M Icosahedral No Bunyaviridae 80–120 Spherical ssRNA, segments Negative Yes L, G1, G2, N, NSM, NSS Helical Yes Reoviridae Rhabdoviridae 60–80 Spherical dsRNA, 12 segments Negative No ? Icosahedral ? Yes 50–100 by 100–400 Bullet ssRNA Negative Yes L, G, N, P, M Helical Yes NA, nucleic acid; ds, double stranded; ?, unknown Biology Alphaviruses The genus Alphavirus in the family Togaviridae contains many members that cause disease throughout the world These viruses can cause classic encephalitis (WEE, EEE, and VEE) or more disseminated disease (Chikungunya [CHIK], o’nyong nyong [ONN], Semliki Forest, Sindbis, RR, Barmah Forest [BF], and Mayaro [MAY]) While these viruses cause a variety of symptoms, their basic biology is identical An excellent and very comprehensive review of alphavirus molecular biology has been published (Strauss and Strauss, 1994) Alphaviruses are small (60 to 70 nm) viruses with a membranederived envelope surrounding an icosahedral nucleocapsid The nucleocapsid encloses one positive-sense single-stranded RNA (ssRNA) molecule of about 12 kDa The genome encodes four nonstructural proteins (nsp1 to nsp 4), the capsid (C) protein, and two virus surface glycoproteins, E1 and E2 Little is known about the early events in alphavirus replication Recent evidence implicates laminin as the alphavirus receptor protein for some cell types (Strauss et al., 1994; Ludwig et al., 1996) Following attachment and endocytosis, the alphavirus must undergo an acid-catalyzed conformational change in its surface glycoproteins that initiates fusion of the viral envelope with the membrane of the endocytic vesicle This fusion process releases the capsid into the cytoplasm and initiates RNA synthesis During replication, the structural proteins (C, E1, and E2) are synthesized from a subgenomic mRNA of about one-third of the total genome This allows for abundant synthesis of the structural proteins for inclusion into progeny virions Progeny viruses bud through cellular membranes that have been modified by the addition of the E1 and E2 glycoproteins to release infectious virions (Strauss et al., 1995) Alphaviruses typically kill infected tissue culture cells within 24 to 48 h Cell death has recently been shown to be through apoptosis (Levine et al., 1994; Ubol et al., 1994; Despres et al., 1995; Levine et al., 1996; Lewis et al., 1996; Griffin and Hardwick, 1997) Alphaviruses are also extremely efficient at shutting down host cell synthesis Alphaviruses grow well in a number of continuous cell lines, such as Vero, BHK-21, and the mosquito cell line C6/36, any of which are acceptable for virus isolation and subsequent characterization protocols In fact, by using inoculation procedures and IFA typing with MAbs, alphaviruses can usually be identified in 24 to 48 h The E2 protein appears to be the virion protein associated with attachment to susceptible cells Preincubation of G R V d e t i n U virus with neutralizing anti-E2 monoclonal antibodies alone will block virus attachment to cells (Roehrig et al., 1982; Roehrig et al., 1988; Roehrig and Mathews, 1985) Because of its ability to elicit neutralizing antibody, the E2 protein is under pressure from the immune response, which results in greater sequence divergence than for other alphavirus proteins It is, therefore, this protein that is most responsible for the specificity of the PRNT in serum from infected individuals The E1 glycoprotein appears to mediate cell membrane fusion and contains alphavirus group-reactive epitopes (Schmaljohn et al., 1983; Boggs et al., 1989) These E1 epitopes serve as the target for the broadly reactive detector MAbs used in the diagnostic ELISA protocols (MAb 2A2C-3 and 1A4B-6) (Roehrig et al., 1982; Roehrig et al., 1990a; Hunt and Roehrig, 1985) Flaviviruses The family Flaviviridae is the family of viruses that is responsible for most arboviral disease This family includes DEN, YF, JE, SLE, and TBE viruses Other medically important flaviviruses are WN, MVE, and POW Flaviviruses are small viruses (40 to 60 nm) composed of an icosahedral nucleocapsid surrounded by a membrane-derived envelope Similar to alphaviruses, the nucleocapsid encloses one positivesense ssRNA molecule of about 10 to 11 kDa This genome encodes three structural proteins, capsid (C), premembrane (prM), and E, and seven nonstructural proteins, NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5 (Rice et al., 1985) Flavivirus attachment and entry are similar to those of alphaviruses, requiring an acid-catalyzed conformational shift in the E glycoprotein to effect membrane fusion and release of capsid into the cytoplasm (Roehrig et al., 1990b; Guirakhoo et al., 1991; Guirakhoo et al., 1992; Guirakhoo et al., 1993) Unlike alphaviruses, flaviviruses not have a subgenomic RNA from which the structural proteins are derived During maturation, the prM protein is cleaved by a furin-like cellular enzyme to M protein, which along with the E glycoprotein, is found in the virion envelope (Stadler et al., 1997) Virus attachment and membrane fusion are both mediated by the E glycoprotein (Guirakhoo et al., 1989; Mandl et al., 1989; Roehrig et al., 1990b) The crystal structure has been solved for the amino-terminal 400-amino-acid fragment of a variety of flaviviruses (Rey et al., 1995; Modis et al., 2003, 2005; Kanai et al., 2006) The three-dimensional structure confirmed much of the biology of the E glycoprotein For a more extensive review of the flavivirus antigenic structure and function, there are a number of good reviews (Heinz, 1986; Roehrig, 1990; Heinz and Mandl, 1993; Heinz and vip.persianss.ir 23 Arboviruses Roehrig, 1990) Unlike alphaviruses, flaviviruses not shut down host cell synthesis In general, flaviviruses infect a number of continuous cell types but are more selective and take longer to grow Many flaviviruses may require up to days for adequate antigen expression Most of the mosquitoborne flaviviruses grow well in the mosquito cell line C6/36 The E glycoprotein elicits virus-neutralizing antibody, so this protein is subjected to immune pressure and, as a result, is responsible for eliciting virus-specific antibody (Peiris et al., 1982; Kimura-Kuroda and Yasui, 1983; Roehrig et al., 1983; Roehrig et al., 1998a; Hawkes et al., 1988; Barrett et al., 1990) This protein also contains epitopes that are flavivirus cross-reactive (Gentry et al., 1982; Henchal et al., 1982; Roehrig et al., 1983; Roehrig et al., 1998a; Henchal et al., 1985; Hawkes et al., 1988) These cross-reactive epitopes serve as the targets for the broadly reactive detector MAbs used in the diagnostic ELISA protocols (MAb 6B6C-1 and 4G2) (Roehrig et al., 1983; Henchal et al., 1985) Bunyaviruses The family Bunyaviridae contains the most vector-borne viruses, only a few of which have been consistently associated with human disease For the United States, the CAL serogroup viruses, primarily LAC encephalitis virus, are the most important pathogens Other bunyaviruses associated with human disease are the Cache Valley (CV), Jamestown Canyon (JC), Snowshoe hare (SSH), Tahyna, Rift Valley fever, and Inkoo viruses The bunyaviruses are larger than either alphaviruses or flaviviruses, about 80 to 120 nm in diameter The virion contains a tripartite genome with three negative-sense ssRNA segments enclosed in helical nucleocapsids surrounded by a lipid envelope (Obijeski et al., 1976b) The L genome segment encodes the l-polymerase, the M genome segment encodes the NSM protein and the two surface glycoproteins G1 and G2, and the S genome segment encodes the nucleocapsid (N) and NSS proteins (Obijeski et al., 1976a; Gentsch et al., 1977; Bishop et al., 1980; Bishop et al., 1982) Because of their tripartite genome, there is a potential that bunyaviruses may undergo genetic reassortment in nature, similar to orthomyxoviruses (Gentsch et al., 1977; Bishop et al., 1978; Bishop, 1979; Gentsch et al., 1979; Bishop and Beaty, 1988; Baldridge et al., 1989; Chandler et al., 1990; Chandler et al., 1991; Urquidi and Bishop, 1992) Coltiviruses to animal handlers, although such transmission has been rare Because of its similarities to rabies virus, the molecular biology of the VSV has been intensely studied, and for detailed reviews, the reader is referred elsewhere (Rodriguez et al., 1993; Katz et al., 1997; Letchworth et al., 1999; Alvarado et al., 2002) Pathogenesis Arboviruses gain entry through the skin by the bite of an infected arthropod; however, some are capable of being transmitted by aerosol in the laboratory setting While the knowledge of the initial events of infection is superficial, evidence is accumulating that early interactions of virus, cells, and mosquito saliva might play some role in the outcome of infection (Zeidner et al., 1999) The mosquito saliva enters the dermis and at times enters the small capillaries directly when the mosquito’s proboscis penetrates the vessel It is presumed that the virus replicates initially in the dermal tissues, including the capillary endothelium, although it is also possible that virus is transported directly in the blood to primary target organs Replication also occurs in the regional lymph nodes, and from there, the blood is seeded, inducing a secondary viremia, which in turn carries virus to infect muscle and connective tissue cells This viremia is often of very high titer and is accompanied by fever, leukopenia, and malaise It is during this viremic phase that an arthropod may feed and become infected The period between infection and viremia (intrinsic incubation period) is usually short, from to days Viremia may last to days CTF viremia is of much longer duration because immature erythrocytes are infected and virus remains in the blood cells for to weeks The vast majority of human arboviral infections are either asymptomatic or self-limited febrile illnesses Antibody is produced and it complexes with and neutralizes circulating virus The process is accompanied by complete recovery and leads to the presence of lifelong antibody Occasionally, however, an infected person develops encephalitis The mechanism of entry of virus into the central nervous system (CNS) is not completely understood Nor is it understood why one person develops encephalitis and another apparently similar individual does not Virus may reach the brain by seeding of cerebral capillaries during viremia and then by direct invasion of the brain parenchyma through the capillary walls Alternatively, certain neural cells, such as the olfactory neurons, are exposed directly to circulating blood; viremia may seed these nerve endings and the virus may pass directly to the olfactory lobe of the brain (Monath et al., 1983) Regardless of the mechanism, it is important to note that the process of seeding the brain and productive infection of brain cells takes time By the time the patient presents with encephalitis, serum antibody is usually detectable, as is antibody, in the CSF At this stage of infection, viremia has ceased and diagnosis is made by serologic assay G R V d e t i n U 395 Little is known about the molecular biology of coltiviruses, which are members of the family Reoviridae The virion is naked (60 to 80 nm) and carries 12 negative-sense doublestranded RNA segments within its nucleocapsid (Knudson, 1981) The specific structure of the virion and its structural proteins has not been defined (Attoui et al., 1997; Attoui et al., 1998) The coding assignments are just now being determined, and the functions of the encoded proteins also have not been well defined Because of the multiple genomic segments, coltiviruses, like bunyaviruses, might be able to undergo genetic reassortment in nature, but this has not been demonstrated to date (Karabatsos et al., 1987) Rhabdoviruses Rhabdoviruses are larger viruses (50 to 100 nm by 100 to 400 nm) and have a characteristic bullet shape Rabies virus is the rhabdovirus of most public health significance; however, the type virus, vesicular stomatitis virus (VSV), has recently been associated with outbreaks in horses and cattle This virus is included here because of it possible transmission Epidemiology Alphaviruses EEE EEE occurs throughout the eastern part of the United States Epidemics of EEE are rare, but a few human cases occur on a regular basis every summer and fall Equine epizootics also can occur in regions as far north as Canada The virus is maintained in nature by an enzootic cycle involving birds and a variety of mosquito species The swampy environments vip.persianss.ir 396 VIRAL PATHOGENS necessary for the EEE vector mosquitoes usually limit the dissemination of this disease Culiseta melanura is the main mosquito infecting birds; human and equine infections are associated with Aedes sollicitans and Aedes vexans in temperate regions and with Aedes taeniorhynchus, Culex taeniopus, and Culex nigripalpus in the tropics A related alphavirus, Highlands J (HJ), also occurs in the eastern United States While it is not frequently associated with human disease, it can confuse the laboratory diagnosis Inapparent cases of EEE are rare Onset is abrupt with high fever, headache, and vomiting followed by drowsiness, coma, and severe convulsions On examination, there is neck stiffness, spasticity, and in infants, bulging fontanels Death may occur within to days of onset Sequelae are common (30%), including convulsions, paralyses, and mental retardation The case/fatality ratio for EEE can reach as high as 30% WEE While the last major United States epidemic of WEE occurred in the 1970s, WEE remains an important cause of encephalitis in North America (Reeves, 1987) The enzootic cycle involves passerine birds—in which the infection is inapparent—and culicine mosquitoes, principally Culex Human cases are first seen in June or July in the Northern Hemisphere, but the mechanism of overwintering of the virus is unknown Children, especially those under year old, are affected more severely than adults and may be left with permanent brain damage, which also is seen in about 5% of adults The mortality rate is about 25% Strains of WEE virus appear to be relatively homogeneous by oligonucleotide fingerprinting and are clearly different from the serologically related HJ virus (Trent and Grant, 1980; Hunt and Roehrig, 1985; Karabatsos et al., 1988) VEE virus was isolated in Venezuela in 1938 from the brain of a horse; like EEE and WEE viruses, it causes encephalitis in members of the family Equidae and humans The enzootic cycle of the VEE virus is still incompletely understood but appears to involve a variety of rodents rather than avian species, which are the hosts of the EEE and WEE viruses Infection of humans is less severe than with the other two alphaviruses, and fatalities are rare Adults usually develop only an influenza-like illness, and overt encephalitis is usually confined to children Six antigenic subtypes of VEE viruses (1 to 6) are now recognized, with subtype being subdivided into five varieties, 1AB to 1F (Calisher et al., 1980; Calisher et al., 1985b; Kinney et al., 1983) Only subtype 1AB and 1C viruses have been associated with major epidemics and epizootics (Powers et al., 1997) The other VEE virus subtypes are involved in enzootic VEE virus transmission (Oberste et al., 1996; Watts et al., 1997; Oberste et al., 1998a; Oberste et al., 1998b; Watts et al., 1998) A major VEE epizootic spread through Central America to reach Texas in 1971, where it was controlled by a massive equine vaccination program, using the live attenuated TC-83 vaccine Over 200,000 horses died in this outbreak, and there were several thousand human infections It is now believed that that epidemic was caused by poorly inactivated vaccine (Sneider et al., 1993; Weaver et al., 1999) The most recent outbreak of epizootic VEE occurred in 1995 in Colombia and Venezuela (Weaver et al., 1996; Rivas et al., 1997) U Flaviviruses WNV G R V WNV was first isolated from the serum of a febrile woman in the West Nile district of Uganda in 1937 Since that time, WNV has circulated in endemic and occasionally epidemic transmission cycles throughout Europe, Western Asia, Africa, the Middle East, Australia (as Kunjin virus), and North and Central America Major outbreaks of WNV have been documented throughout the world In 1999, a WNV outbreak was recognized in the United States for the first time This initial human and animal outbreak was identified in the New York City area Genetic studies determined that this virus introduction likely occurred from the Middle East, most likely from Israel (Lanciotti et al., 1999) Since that time, WNV has spread westward through the entire continental United States and into Canada, Mexico, Central America, South America, and some Caribbean islands WNV now accounts for the largest number of cases of viral encephalitis in the United States Worldwide, WNV is an arbovirus, primarily transmitted by the mosquitoes of the genus Culex (e.g., Culex tarsalis, Culex pipiens pipiens, Culex pipiens quinquefasciatus, Culex salinarius, and Culex nigirpalpus in the United States) Mosquito-borne transmission to humans in temperate climates usually peaks in the late summer and early fall Mosquito-borne transmission to humans in milder or more tropical climates can occur throughout the year, whenever mosquitoes are active In the United States alone, however, 59 species of mosquitoes have been shown to be infected with WNV The actual vector status of many of these mosquito species remains to be determined WNV is a zoonotic disease with birds being the primary natural reservoir Over 300 species of birds have been shown to be infected with WNV in the Western Hemisphere Humans are primarily infected through the bite of a WNV-infected mosquito Recently, other modes of WNV transmission have been identified, such as blood transfusion, tissue transplantation, percutaneous occupational exposure, breastfeeding, and intrauterine transfer (Hayes and O’Leary, 2004) The last two modes of transmission have been documented but are very rare (O’Leary et al., 2006; Paisley et al., 2006) Even though WNV has now been in the United States since 1999, molecular epidemiological analysis of current and past strains of the United States WNV has demonstrated low-level genetic drift, with remarkable overall phenotypic stability (Lanciotti et al., 1999; Lanciotti et al., 2002; Davis et al., 2005) WNV can be divided into two genetic lineages (1 and 2), with lineage WNVs primarily responsible for major human outbreaks Lineage strains have been d e t i n VEE CHIK, ONN, and MAY are mosquito-transmitted rash diseases These viruses cause a fairly debilitating acute infection in Africa, Asia, and South America The disease symptoms usually include headache, fever, rash, and myalgia, but it is not fatal The mosquito vectors for CHIK (Aedes aegypti) and ONN (Aedes gambiae and Anopheles funestus) are known The human mosquito vector for MAY has not been well defined, however, Haemagogus sp mosquitoes likely maintain the sylvatic cycle RR and BF viruses are the major causes of polyarthritis in Australia The mosquito vectors are not well defined and vary across Australia It is believed that the primary vectors are members of the Aedes, Culex, and Oclerotatus genera Similar to CHIK, ONN, and MAY, acute infection with RR or BF can be debilitating; however, it is not fatal Other Medically Important Alphaviruses CHIK, ONN, MAY, RR, and BF viruses are exotic alphaviruses with potential for importation into the United States vip.persianss.ir 678 SUBJECT INDEX Dengue (DEN) virus infections diagnosis of, 391–393 flow cytometry, 195–196 IgM assay, 128 immunohistochemistry, 107 specimen collection for, 22 epidemiology of, 397 risk factors for, 393 susceptibility testing in, 190–191 Dengue hemorrhagic fever, 387, 397 Dengue shock syndrome, 387, 397 Densonucleosis viruses, 546 Dependoviruses, 546 Dermal swabs, 21, 23, 25–27 Dermatitis HSV, 433–434 infective, HTLV-associated, 607 DFA, see Direct immunofluorescence Diabetes mellitus, due to congenital rubella virus, 570 Diarrhea, see also Gastroenteritis in enterovirus infections, 259 in SARS-CoV infections, 226 Didanosine, susceptibility testing of, 138 Dideoxynucleotide sequencing, in susceptibility testing, 139–140 Digene hybrid capture test, for chlamydiae, 634 Direct antigen tests, quality assurance for, 10–11 Direct immunofluorescence, 78–79, 81–82 for chlamydiae, 634 for rabies virus, 370–372 Direct-application method, electron microscopy of, 67 Directigen EIA system, 93, 97 Disinfectants for enteroviruses, 253, 255 for retroviruses, 579 District of Columbia, virology services in, 666 DNA hybridization, in susceptibility testing, 136–137 DNA microarray, 164–165 Dobrava-Belgrade virus (DOBV), 643, 648 “Doctrine of original antigenic sin,” 213 Documentation, 4, 9, 15 Dogs, rabies virus infections in, 363, 366–368, 375, 378 Dot immunobinding assay, for mumps virus, 568 Double-antigen sandwich assay, for HIV, 589–590 Doxycycline, for chlamydial infections, 636 Droplet transmission, of viruses, 205–206 Drug(s), hypersensitivity due to, in HHV-6 infections, 499–500 Drug resistance, see Antiviral drugs, resistance to Duvenhage virus, 364, 368 Dye uptake assay, in susceptibility testing, 136 of urine specimens, 71 of VZV, 68, 69, 71, 73 water drop method for, 67 Electropherotyping, of rotaviruses, 288 Elementary bodies, Chlamydia, 631, 633–634 ELISA (enzyme-linked immunosorbent assay) antigen-capture, 391, 392 for arboviruses, 388, 390–392 for arenaviruses, 648 for astroviruses, 293 blocking, 390 for caliciviruses, 291 for enteroviruses, 267 for GBV-C, 352–353 for HEV, 318 for HHV-8, 509 for HIV, 589 for HSV, 440–441 for HTLV, 608–610 IgG, 390, 391 IgM-capture, 390, 391 for mumps virus, 568 for parvovirus B19, 552 for rabies virus, 371, 375 for rotavirus, 288 ELVIS (enzyme-linked inducible system), 44, 45, 441 E-mix, of cell cultures, 44 Encephalitis arbovirus, 387 Dawson’s, 563 enterovirus, 258–259 HHV-6, 499, 500, 502 HMPV, 219 HSV, 431, 434, 435 measles virus, 563 mumps virus, 567 rabies virus, 363, 365–366, 373–374 rubella virus, 570 Encephalopathy HAV, 314 HEV, 314 HHV-6, 500 Enfuviritide, susceptibility testing of, 140–141 Entecavir for HBV infections, 333 susceptibility testing of, 141–142 Enterotoxins, rotavirus, 286 Enterovirus(es), 249–282; see also specific viruses, e.g., Poliovirus antigenicity of, 251, 253 biology of, 251–255 classification of, 250–251 discovery of, 249 immune response to, 260 reactivity of, to environmental agents, 253, 255 receptors for, 255 transmission of, 260–262 vaccines for, 267–268 Enterovirus infections, 249–282 acute conjunctivitis in, 259 asymptomatic, 255 clinical features of, 255–260 diagnosis of, 262–267 cell culture, 41, 43, 45–47, 255 hemagglutination inhibition test, 120 immunofluorescence assay, 80 isolation of, 264–265 molecular, 265–266 G R V d e t i n U E EA (early antigen), EBV, 472 Eastern equine encephalitis (EEE) virus biology of, 394 history of, 387 vaccines for, 398 Eastern equine encephalitis (EEE) virus infections diagnosis of, 390–393 epidemiology of, 395–396 EBER antigens, 469–470 EBNAs (Epstein-Barr nuclear antigens), 469–472 EBV, see Epstein-Barr virus entries Echovirus(es) antigenicity of, 251 classification of, 250 discovery of, 249 incubation time of, 255 neutralization test for, 115 Ectromelia virus, 529, 530 Eczema, HTLV-associated, 607 Eczema herpeticum, 433 EEE virus, see Eastern equine encephalitis virus entries EIAs, see Enzyme immunoassays (EIAs) Elderly persons influenza virus infections in, 211 parainfluenza virus infections in, 221 respiratory virus susceptibility of, 206 Electron microscopy, 64–76 of adenoviruses, 65, 68 advantages of, 73 agar diffusion method in, 67 Airfuge ultracentrifugation in, 67–68 of astroviruses, 65, 68, 72, 293 of calicivirus, 65, 68, 291 of Campylobacter, 69 of cell cultures, 71 of cerebrospinal fluid specimens, 71 of CMV, 71 of coronaviruses, 65, 68 direct-application method for, 67 of gastrointestinal tract specimens, 65, 71 of hand, foot, and mouth disease, 68 of HAV, 71 of HBV, 71, 72 of hendraviruses, 73 history of, 64 of HMPV, 74 of HSV, 68, 69 immunoelectron microscopy, 64, 71–73 immunogold, 72–73 of influenza virus, 68, 70 limitations of, 73 of molluscum contagiosum virus, 68, 69 morphological features of, 68 of mumps virus, 71 of Mycoplasma hyorrhinis, 70 negative staining methods in, 65–67 of norovirus, 68, 71 of norovirus-like particles, 71–72 of Norwalk-like virus, 65 of papillomaviruses, 71 of papovavirus, 69, 71 of parainfluenza virus, 70 of paramyxoviruses, 68, 71 of parapoxviruses, 68 of parvovirus B19, 551–552 of poxviruses, 526 principles of, 64–67 of reovirus, 66, 68 of respiratory tract specimens, 68–67, 71 of rotaviruses, 66, 68, 71, 72, 288 of RSV, 68, 70 of rubella virus, 68, 70, 71 of sapovirus, 68 of SARS-CoV, 73–74 of skin lesions, 68 of stool specimens, 68–69, 71 tips for, 73–75 of toroviruses, 68 of torovirus-like particles, 65 vip.persianss.ir SUBJECT INDEX neutralization test, 110, 114–115, 117, 253 serologic, 266–267 diarrhea in, 259 encephalitis in, 258–259 epidemiology of, 260–264 gastroenteritis in, 295 hand-foot-mouth disease in, 259 herpangina in, 259 incubation period for, 255 meningitis in, 257–258 myocarditis in, 259 neonatal, 259–260 paralytic myelitis in, 257 pathogenesis of, 255–260 pericarditis in, 259 pleurodynia in, 259 poliomyelitis in, see Poliomyelitis prevention of, 267–268 rash in, 259 respiratory disease in, 259–260 specimen collection in, 20, 21, 25, 28 treatment of, 268, 270 vaccines for, 267–268 Environment, enteroviruses in, 261 Enzyme immunoassays (EIAs), 89–102 automation of, 92–93 bead-based, 90–91 biotin-avidin, 91–92 chemiluminescence, 91–92 for chlamydiae, 634 competitive solid-phase, 91 for HBV, 334–335 for HCV, 343 for HHV-7, 504 history of, 89 for HTLV, 609 IgM- and IgA-specific, 99 immunoblotting, 90 immunochromatography, see Immunochromatography vs immunofluorescence, 79 immunoglobulin M, 128 immunoperoxidase staining (histochemical), 89–90 for measles virus, 564–565 membrane, 93 noncompetitive solid-phase, 90–91 nucleic acid amplification, 160–162 optical immunoassay, 93–94 quality control in, 99–100 reporting results, 99–100 for rubella virus, 571 in susceptibility testing, 137 tube-based, 90–91 for viral antibody detection, 99 for viral antigen detection, 95–99 Enzyme-linked inducible system, 44, 45, 441 Eosinophilia, with drug reaction, in HHV-6 infections, 499–500 Epidermodysplasia verruciformis, 409–410 Epididymitis, Chlamydia trachomatis, 632 Epilepsy, temporal lobe, in HHV-6 infections, 500 Epstein-Barr virus (EBV), 469–473 antigens of, 469–472 biology of, 469–470 history of, 469 strains of, 470 susceptibility testing of, 191–193 transmission of, 470 Epstein-Barr virus (EBV) infections clinical features of, 470–472 diagnosis of, 472–473 flow cytometry, 191–192 quantitative molecular techniques, 179 specimen collection for, 22–23 epidemiology of, 470 treatment of, 473 Equine encephalitis viruses, see Eastern equine encephalitis (EEE) virus; Venezuelan equine encephalitis (VEE) virus; Western equine encephalitis (WEE) virus Equipment, quality assurance, 9–11 Erythema infectiosum, 548 Erythema multiforme, HSV-associated, 433–434 Erythromycin, for chlamydial infections, 636 Erythroviruses, 546 Escherichia coli, in IgM determination, 129 Etoposide, for ATLL, 611, 611Vindesine Exanthem in enterovirus infections, 259 specimen collection from, 21 Exanthem subitum, 494 Eye infections, see Ocular infections EZ Fu A/B method, 97 U in susceptibility testing, 188–195 in virus receptor detection, 197 Flu-like illness in arenavirus infections, 644 in HIV infection, 588 in parvovirus B19 infections, 547–548 in rhinovirus infections, 223 viruses causing, 204 Fluorescein isothiocyanate, 77, 78, 81, 85 Fluorescence, definition of, 77 Fluorescence immunoassay, see Immunofluorescence assay Fluorescent antibody staining, for chlamydiae, 633–634 Fluorescent antibody virus neutralization test, for rabies virus, 375 Fluorescent focus inhibition test, rabies, 375 Fluorescent-antibody-to-membraneantigen (FAMA) test, for VZV, 467 Fluorochromes in flow cytometry, 185–200 for immunofluorescence, 77–78 Folliculitis, HSV, 434 Fomites, in viral transmission, 205–206 Fomivirsen, for CMV infections, 460 Food enteroviruses in, 261 hepatitis viruses in, see Hepatitis A virus (HAV); Hepatitis E virus (HEV) noroviruses in, 290 Foscarnet for CMV infections, 460 for HHV-6 infections, 502–503 for HHV-8 infections, 510 susceptibility testing of, 134, 137, 139 for VZV infections, 467 FRET system, 163, 171 G R V F FAMA (fluorescent-antibody-to-membraneantigen) test, for VZV, 467 Famciclovir for HSV infections, 444–445 susceptibility testing of, 137 for VZV infections, 467 Fatal brain stem encephalitis, 258 Fecal specimens collection of, 28 electron microscopy of, 68–69, 71 Feline calicivirus, 288 Fever blisters, 433 Fifth disease (erythema infectiosum), 548 Filtration, cytology, 53 Fixation for immunofluorescence assay, 80–81 for immunohistochemistry, 104 Flavivirus(es) biology of, 394–395 identification of, 391 susceptibility testing of, 190–191 types of, 388 Flavivirus infections diagnosis of, 190–191, 389 epidemiology of, 396–397 Flexal virus, 643 Florida, virology services in, 666 Flow cytometry, 185–200 in apoptosis, 188 in cell culture analysis, 186–188 in cell cycle analysis, 188 in CMV infections, 188–190 definition of, 185–186 in dengue virus infections, 195–196 equipment for, 186 in flavivirus infections, 190–191 in HCV infections, 186–187, 197 history of, 185 in HIV infection, 188, 193–197 in influenza virus infections, 193 in lymphotropic herpesvirus infections, 191–193 in multiparametric analysis, 197 d e t i n 679 G Ganciclovir for CMV infections, 460 for HHV-6 infections, 502–503 for HHV-8 infections, 510 resistance to, 503 susceptibility testing of, 134, 139, 189 Gastroenteritis adenovirus, 284, 293–294 Aichi, 294–295 astrovirus, 284, 292–293 becovirus, 289 Berne virus, 294 Breda virus, 294 calicivirus, 288–292 CoV, 225, 294 enterovirus, 259, 295 HIV, 295 kobuvirus, 295 lagovirus, 289 norovirus, 284, 288–292 picornavirus, 284, 294 recovirus, 289 rotavirus, 283–288 sapovirus, 284, 289, 290 SARS-CoV, 226 torovirus, 284, 294 vesivirus, 289 Gastrointestinal tract, specimens from, see also Stool specimens electron microscopy of, 65, 71 GBV-C, see Hepatitis G virus (HGV), 350–353 Gel chromatography, for poxviruses, 528 vip.persianss.ir 680 SUBJECT INDEX Gene therapy, HSV vector for, 446 GeneSeq HIV assay, 140 Genital swabs, 21, 24 Genital tract infections chlamydial, 631–632, 636 cytopathology of, 57–60 HIV, 584–585 HPV (warts), 409, 411, 414 HSV, see HSV-2 infections molluscum contagiosum virus, 535–536 pelvic inflammatory disease, 631–632 specimen collection in, 21, 24 Genotypic assays, in antiviral susceptibility testing, 135–136, 139–142 Georgia, virology services in, 666 German measles, see Rubella virus infections Gingivostomatitis, HSV, 433 Glaucoma, due to congenital rubella virus, 570 Government Accounting Office (GAO), 14–15 gp41, HIV binding to, 582 gp120, HIV binding to, 582 Green fluorescent protein, in neutralization test, 112 Ground-glass appearance, HSV infections, 58–59 Guanarito arenavirus, see GUAV Guanarito arenavirus (GUAV), 641, 643 Guanarito arenavirus (GUAV) infections diagnosis of, 648 pathogenesis of, 644 GUAV, see Guanarito arenavirus entries Gut-associated lymphoid tissue (GALT), HIV in, 586 H HAART (highly active antiretroviral therapy) immune reconstitution syndrome in, 456 Kaposi’s sarcoma exacerbation in, 509–510 monitoring of, 599–600 polyomavirus infection improvement due to, 421 HAI, see Hemaggluination inhibition test HAM/STP (HTLV-associated myelopathy/tropical spastic paraparesis), 605–606 Hand, foot, and mouth disease, 68, 259 Hand-washing, for viral transmission interruption, 206 Hantaan virus (HTNV), 643 biology of, 642 vaccines for, 650 Hantaan virus (HTNV) infections diagnosis of, 648 pathogenesis of, 645–646 Hantavirus(es), 641–657 animal models of, 642 biology of, 642, 644 distribution of, 643 genome of, 642, 644 hosts of, 643 overview of, 641–642 taxonomy of, 642 transmission of, 641 Hantavirus cardiopulmonary syndrome (HCPS), 641, 647–650 Hantavirus infections diagnosis of, 648–649 epidemiology of, 646–648 pathogenesis of, 641–643, 645–646 prevention of, 649–650 treatment of, 650 HastV, see Human astrovirus HAU (HTLV-associated uveitis), 607 HAV, see Hepatitis A virus (HAV) Hawaii, virology services in, 666 HBcAg (hepatitis B core antigen), 331 HBeAg (hepatitis B e antigen), 328, 330, 332, 334–335 HboV, see Human bocavirus (HBoV) entries HBsAg (hepatitis B surface antigen), 327, 330, 332, 334 HBV, see Hepatitis B virus (HBV) entries HCMV, see Cytomegalovirus (CMV) HCPS, see Hantavirus cardiopulmonary syndrome HCV, see Hepatitis C virus (HCV) entries HCV core antigen, 344–345 HDAg protein, 347 HDV, see Hepatitis D virus (HDV) entries Headache, in rabies virus infection, 366 Heart inflammation of, see Myocarditis transplantation of, HHV-6 infections after, 498 Heart-lung transplantation, HHV-6 infections after, 498 Heat, for enterovirus inactivation, 253, 255 Heat shock proteins, in chlamydial infections, 632 Hemadsorption, 38, 41, 119 Hemagglutination inhibition test, 120–122 for arboviruses, 389 for measles virus, 565 for mumps virus, 568 Hemolytic anemia, in parvovirus B19 infections, 548, 549 Hemorrhagic cystitis, after transplantation, 421 Hemorrhagic fever(s) Argentinian, 646, 650 Bolivian, 645 Crimean-Congo, 398 dengue, 387, 397 pathogenesis of, 644 renal syndrome with, 645–646, 648–649 Venezuelan, 641, 646 Hemorrhagic fever with renal syndrome (HFRS) clinical features of, 645 diagnosis of, 648–649 pathogenesis of, 645–646 Hendraviruses, 73 Hepatitis arenavirus, 645 HSV, 434 waterborne, see Hepatitis A virus (HAV); Hepatitis E virus (HEV) Hepatitis A virus (HAV) biology of, 311–313 immune response to, 314–315 vaccines for, 318–320 Hepatitis A virus (HAV) infections clinical features of, 313–314 diagnosis of, 317–318, 666–667 electron microscopy, 71 epidemiology of, 315 natural history of, 314 pathogenesis of, 313–315 prevention of, 318–320 specimen collection in, 23 U G R V d e t i n Hepatitis B core antigen (HBcAg), 331 Hepatitis B e antigen (HBeAg), 328, 330, 332, 334–335 Hepatitis B surface antigen (HBsAg), 327, 330, 332, 334 Hepatitis B virus (HBV) antibodies to, 327, 331, 334–336 antigens of, 327–328, 330–335 biology of, 327–329 carriers of, 325 drug resistance in, 334, 336 genotypes of, 330, 336 immune response to, 327–332 susceptibility testing of, 134–136, 141–142 transmission of, 333 vaccines for, 333 Hepatitis B virus (HBV) infections acute, 325–326 chronic, 325–326, 332 clinical features of, 325–326, 330 coinfections with, 326 diagnosis of, 326–327, 334–336 DNA detection, 335–336 electron microscopy, 71, 72 enzyme immunoassay, 95, 99 immunohistochemistry, 106 quantitative molecular techniques, 178 state laboratory services for, 666–667 epidemiology of, 332–333 extrahepatic manifestations of, 326 HDV infections with, 345, 347 hepatocellular carcinoma in, 326, 332 occult, 332 prevention of, 333–334 self-limited acute, 330–332 specimen collection in, 23 treatment of, 332–334 Hepatitis C virus (HCV), 337–345 antibodies to, 340–341, 343–344 antigens of, 344–345 biology of, 337–338 carriers of, 325 genotypes of, 337–338, 341, 345 immune response to, 340–341 quasispecies of, 345 RNA of, measurement of, 344 susceptibility testing of, 186–187 transmission of, 341 vaccines for, 341–342 Hepatitis C virus (HCV) infections acute, 325–326 chronic, 325–326, 340–341 clinical features of, 325–326, 338–341 coinfections with, 326 diagnosis of, 326–327, 343–345 immunoblotting, 90 PCR, 170 quantitative molecular techniques, 170, 176 RNA measurement, 343–344 state laboratory services for, 666–667 epidemiology of, 341 extrahepatic manifestations of, 326 flow cytometry in, 186–187, 197 hepatocellular carcinoma in, 326 occult, 340 prevention of, 341–342 self-limited acute, 338–340 specimen collection in, 23 treatment of, 342–343 vip.persianss.ir SUBJECT INDEX Hepatitis D virus (HDV), 345–350 antibodies to, 349–350 antigens of, 347, 350 biology of, 345–347 carriers of, 325 genotypes of, 350 immune response to, 347 RNA of, measurement of, 350 transmission of, 349 Hepatitis D virus (HDV) infections acute, 325–326 chronic, 325–326 clinical features of, 325–326 coinfections with, 326, 347–348 diagnosis of, 326–327, 349–350 epidemiology of, 349 extrahepatic manifestations of, 326 hepatocellular carcinoma in, 326 pathogenesis of, 347 prevention of, 349 specimen collection in, 23 superinfections with, 348–349 treatment of, 349 Hepatitis E virus (HEV) biology of, 311–313 immune response to, 314–315 vaccines for, 319–320 zoonotic reservoir of, 317 Hepatitis E virus (HEV) infections clinical features of, 313–314 diagnosis of, 317–318 epidemiology of, 315–317 natural history of, 314 pathogenesis of, 313–315 in pregnancy, 320 prevention of, 318–320 specimen collection in, 23 Hepatitis G virus (HGV, GBV-C), 350–353 Hepatocellular carcinoma, 326 Herpangina, 259 Herpes dermatitis, 433–434 Herpes folliculitis, 434 Herpes gladiatorum, 433 Herpes labialis/facialis/febrilis, 433 Herpes simplex virus (HSV), 424–453; see also Herpes simplex virus type (HSV-1); Herpes simplex virus type (HSV-2) classification of, 424 discovery of, 424 erythema multiforme associated with, 433–434 as gene therapy vector, 446–447 genetic information of, 424–425 immune response to, 442–444 polymorphism of, 425 replication of, 425–431 structure of, 424–425 susceptibility testing of, 134–138, 143 tissue tropism of, 432–433 transmission of, 432–433, 446–447 Herpes simplex virus (HSV) infections asymptomatic, 431–432 clinical features of, 432–439 cytopathology of, 53–54, 56–58, 61 diagnosis of, 439–442 antigen detection, 440–441 cell culture, 38, 43–45, 440 cytology, 439–440 electron microscopy, 68, 69 histopathology, 439–440 immunofluorescence, 78, 79, 82 immunohistochemistry, 106 neutralization test, 110 nucleic acid testing, 441–442 serology, 442 encephalitis in, 431 epidemiology of, 431–432 HIV infection with, 434 latency in, 435–439 neonatal, 433, 435 neoplastic transformation in, 439 in pregnancy, 435 reactivation in, 437–439 risk factors for, 431–432 specimen collection in, 19, 21, 24–28 treatment of, 444–447 Herpes simplex virus type (HSV-1) clinical syndromes due to, 431–432 description of, 424 host cell effects of, 430–431 polymorphism of, 425 replication of, 425–431 risk factors for, 431–432 tissue tropism of, 432–433 transmission of, 431 Herpes simplex virus type (HSV-1) infections clinical features of, 432–439 diagnosis of, 79, 439–442 epidemiology of, 431 latency in, 435–439 neoplastic transformation in, 439 in pregnancy, 435 reactivation in, 437–439 structure of, 424–425 treatment of, 446–447 Herpes simplex virus type (HSV-2) description of, 424 host cell effects of, 430–431 polymorphism of, 425 replication of, 429–431 tissue tropism of, 432–433 transmission of, 431 vaccines for, 443–444 Herpes simplex virus type (HSV-2) infections clinical features of, 432–439 diagnosis of, 439–442 epidemiology of, 431–432 latency in, 435–439 neonatal, 435 neoplastic transformation in, 439 in pregnancy, 435 reactivation in, 437–439 risk factors for, 431–432 structure of, 424–425 treatment of, 444–446 Herpes zoster, 464–465, 469; see also Varicella-zoster virus (VZV) Herpes zoster keratitis, 61 Herpetic whitlow, 433 HEV, see Hepatitis E virus (HEV) HFRS, see Hemorrhagic fever with renal syndrome (HFRS) HGV, see Hepatitis G virus (HGV, GBV-C), 350–353 HHV-1, see Herpes simplex virus type (HSV-1) HHV-2, see Herpes simplex virus type (HSV-2) HHV-3, see Varicella-zoster virus (VZV) HHV-4, see Epstein-Barr virus (EBV) HHV-5, see Cytomegalovirus (CMV) HHV-6, see Human herpesvirus (HHV-6) entries U HHV-7, see Human herpesvirus (HHV-7) entries HHV-8, see Human herpesvirus (HHV-8) entries HI test, see Hemagglutination inhibition test Highly active antiretroviral therapy, see HAART Histochemical enzyme immunoassay, 89–90 Histologic examination for poxviruses, 526 for rabies virus, 371 Histopathology in CVM infections, 458 in HSV infections, 439–440 HIV (human immunodeficiency virus), 578–579 biology of, 579–588 diversity of, 584 gene transcription in, 584 genome of, 582 groups of, 581–582 host cell entry by, 582–584 immune response to, 583–588 latency in, 588 origin of, 580–581 quasispecies of, 584 replication of, 582–584 subtypes of, 581–582 susceptibility testing of, 134–141, 193–195 transmission of, 578–579, 584–586 type 1, see HIV-1 type 2, see HIV-2 HIV (human immunodeficiency virus) infection acute, 586–588 acute retroviral syndrome in, 588 AIDS defining, criteria for, 588, 612 chronic, 586–588 clinical features of, 588, 612 CMV infections with, 179, 456–457 diagnosis of, 588–598 algorithms for, 596 bDNA, 594–595 cell culture, 595 criteria for, 612 DNA, 593–595 enzyme immunoassay, 99 flow cytometry, 188, 193–197 immunoblotting, 90 LIA, 591–592 NASBA, 173, 594 nucleic acid tests, 593 other than U.S., 596, 598 p24 antigen test, 593 PCR, 170–171, 593–594 quantitative molecular techniques, 170, 174, 177–178 reference testing, 661–662 RNA, 589, 593–595 RT assays, 595–596 safety in, 578–579 screening, 589–591 specimen collection for, 24 TMA, 594 U.S guidelines for, 596–597 viral load assays, 169, 178, 599–600 Western blotting, 150, 154, 591–593, 596 early window periods in, 589 EBV infections with, 471 epidemiology of, 579–588 G R V d e t i n 681 vip.persianss.ir 682 SUBJECT INDEX HIV (human immunodeficiency virus) infection (continued) gastroenteritis in, 295 generalized, 434 HBV infections with, 326 HCV infections with, 326 hepatitis with, 326 HHV-6 infections with, 499 HHV-8 infections with, 508–510 HMPV infections with, 219 HSV infections with, 431–432 Kaposi’s sarcoma in, 508–510 lymphoma in, 471 nonprogressors and progressors in, 588 pathogenesis of, 584–588 in pediatric patients, 588, 598 prognosis for, 599 progressive multifocal leukoencephalopathy in, 419–420 respiratory infections with, 207 seroconversion in, 589, 591 treatment of, 588 drug resistance testing in, 600–601 monitoring of, 598–600 viral load in, 599 VZV infections with, 465 HIV-1 (human immunodeficiency virus type 1) diversity of, 584 gene transcription in, 584 genome of, 582 origin of, 580–581 replication of, 582–584 subtypes of, 582 transmission of, 584–586 HIV-1 (human immunodeficiency virus type 1) infection acute, 586–588 biology of, 579–588 chronic, 586–588 diagnosis of bDNA, 594–595 LIA, 589–591 NASBA, 594 nucleic acid tests, 593 other than U.S., 596, 598 p24 antigen test, 593 screening, 589–591 U.S guidelines for, 596–597 Western blotting, 589–591 HIV-2 (human immunodeficiency virus type 2) genome of, 582 origin of, 581 replication of, 582–584 subtypes of, 582 HIV-2 (human immunodeficiency virus type 2) infection biology of, 579, 581–582 diagnosis of, 596 immunoblotting, 90 other than U.S., 596, 598 pediatric, 598 rapid tests for, 591 screening, 589–591 U.S guidelines for, 596–597 Western blotting, 592 HMPV, see Human metapneumovirus (HMPV) entries Hodgkin’s lymphoma, 472 Host systems, for neutralization test, 113–114 HPA, see Hybridization protection assay HpeV, see Human parechovirus (HPeV) entries HPV, see Human papillomavirus (HPV) entries HSV, see Herpes simplex virus (HSV) entries HTLV, see Human T-cell lymphotropic virus (HTLV) entries HTNV, see Hantaan virus (HTNV) entries HuCVs, see Human caliciviruses (HuCVs) Human astrovirus (HastV), 24, 65, 68, 72, 292–293 Human bocavirus (HboV), 205, 229–230 Human bocavirus (HBoV) infections, 26, 554 Human caliciviruses (HuCVs), 65, 68, 288–292 Human foamy virus, 579 Human herpesvirus (HHV-6), 494–503 biology of, 494–495 discovery of, 494 genome of, 494–495 growth cycle of, 495 immune response to, 497 receptors for, 495 susceptibility testing of, 191–193 tissue distribution of, 495 transmission of, 495–496 variants (A and B) of, 494 Human herpesvirus (HHV-6) infections clinical features of, 496–500 diagnosis of, 500–502 flow cytometry, 191–193 immunofluorescence, 80 quantitative molecular techniques, 179 disseminated, 498 drug-induced hypersensitivity syndrome in, 499–500 encephalitis or encephalopathy in, 500, 502 epidemiology of, 495–496 in immunodeficiency, 498–499 multiple sclerosis in, 497, 500 myocarditis in, 499 pathogenesis of, 496–497 primary, 497–498 taxonomy of, 495 temporal medial lobe epilepsy in, 500 treatment of, 502–503 Human herpesvirus (HHV-7), 504–505 discovery of, 494 tissue distribution of, 495 Human herpesvirus (HHV-7) infections, 504–505 diagnosis of immunofluorescence, 80 quantitative molecular techniques, 179 Human herpesvirus (HHV-8), 504–510 biology of, 504–506 discovery of, 494, 504 susceptibility testing of, 191–193 tissue distribution of, 495 transmission of, 506–507 Human herpesvirus (HHV-8) infections clinical features of, 507–508 diagnosis of, 508–509 flow cytometry, 191–193 immunohistochemistry, 106 quantitative molecular techniques, 179 epidemiology of, 506–507 Kaposi’s sarcoma in, 504, 506–510 multicentric Castleman’s disease, 508 pathogenesis of, 507–508 PEL, 508 prevention of, 509–510 primary, 507 U G R V d e t i n primary effusion lymphoma, 508 treatment of, 509–510 Human immunodeficiency virus, see HIV Human metapneumovirus (HMPV), 218–220 biology of, 218 subgroups of, 218 transmission of, 219–220 vaccines for, 220 Human metapneumovirus (HMPV) infections, 218–220 clinical features of, 204, 218–219 coinfections with, 219 diagnosis of, 208, 220 electron microscopy, 74 immunofluorescence, 78, 80 specimen collection for, 20, 26 epidemiology of, 204 recurrent, 219 RSV comparison with, 218–219 treatment of, 220 Human papillomavirus (HPV), 408–416 biology of, 408 genotypes of, 409 transmission of, 409 type 1, 410 type 2, 410 type 3, 409, 410 type 4, 410 type 5, 409, 410 type 6, 410–412, 414 type 8, 409, 410 type 10, 409, 410 type 11, 409–412, 414 type 13, 409, 410 type 14, 410 type 16, 409, 412, 414 type 18, 409, 412, 414 type 31, 412 type 32, 410 type 33, 412 type 35, 412 type 39, 412 type 41, 414 type 42, 414 type 43, 414 type 45, 412 type 52, 412 type 58, 412 type 59, 412 type 68, 412 vaccines for, 414 Human papillomavirus (HPV) infections cervical cancer, 412, 414 cutaneous, 410–411 cytopathology of, 58–60 diagnosis of, 106, 412–414 epidermodysplasia verruciformis, 409–410 genital cancers, 412 host factors in, 409 lesion location in, 409 mucosal, 411–412 oral lesions, 412 oropharyngeal cancer, 412 pathogenesis of, 408–410 recurrent respiratory papillomatosis, 411–412 skin cancers, 410–411 specimen collection in, 24 tonsillar cancer, 412 treatment of, 414 warts, 408–414 vip.persianss.ir SUBJECT INDEX Human parechovirus (HPeV), 250 structure of, 251 transmission of, 261 Human parechovirus (HPeV) infections diagnosis of, 264–265, 267 encephalitis in, 258 Human polyomaviruses, see Polyomavirus(es) Human T-cell lymphotropic virus (HTLV), 601–612 biology of, 601–604 carriers of, 604 discovery of, 578 genome of, 601–603 overview of, 579 proteins of, 601–603 subtypes of, 601 transmission of, 578–579, 608 types of, 601 Human T-cell lymphotropic virus (HTLV) infections adult T-cell leukemia or lymphoma, 604–605, 611–612 arthritis associated with, 607 bronchopneumopathy associated with, 607 diagnosis of, 608–611 cell culture, 610–611 ELISA, 610 immunoblotting for, 90 LIA, 609 PCR, 609–611 provirus load, 611 safety in, 578–579 screening, 608–609 Western blotting, 150, 609–610 epidemiology of, 608 hematologic diseases associated with, 607 infective dermatitis in, 607 inflammatory disorders in, 605 myelopathy/tropical spastic paraparesis (HAM/TSP) associated with, 605–606 pathogenesis of, 603–604 treatment of, 611–612 uveitis in, 605–606 Human T-cell lymphotropic virus type (HTLV-1) biology of, 601–604 transmission of, 608 Human T-cell lymphotropic virus type (HTLV-1) infections diagnosis of, 608–611 diseases associated with, 604–607 epidemiology of, 608 pathogenesis of, 603–607 treatment of, 611–612 Human T-cell lymphotropic virus type (HTLV-2) biology of, 601–604 transmission of, 608 Human T-cell lymphotropic virus type (HTLV-2) infections diagnosis of, 608–611 diseases associated with, 607–608 epidemiology of, 608 Human T-cell lymphotropic virus type 3, 601 Human T-cell lymphotropic virus type 4, 601 Hybrid capture assay, 160–162, 176, 414 Hybridization probes, 163–164 Hybridization protection assay (HPA), 162 Hydrolysis probes, 163 Hydrophobia, in rabies virus infection, 366 Hydrops fetalis, in parvovirus B19 infections, 549, 553–554 Hypercalcemia, in ATLL, 605 Hypersensitivity, drug-induced, in HHV-6 infections, 499–500 I ICH, see Immunohistochemistry (ICH) ICR, see Immunochromatography Idaho, virology services in, 666 IDH (infective dermatitis), HTLV-associated, 607 IEM, see Immunoelectron microscopy IFA, see Immunofluorescence assay Igs, see Immunoglobulin(s) Illinois, virology services in, 666 ILO, see International Organization for Standardization (ILO), Immune reconstitution syndrome, in CMV infections, 456 Immune response, see specific viruses Immunoassays, see also Immunofluorescence assay for arboviruses, 390 for astroviruses, 293 for caliciviruses, 291 capture, 128 enzyme, see Enzyme immunoassays (EIAs) for IgM, 124–133 for influenza virus, 213 microsphere, 390 optical, 93–99, 635 for parvovirus B19, 552 radioimmunoassay, 552 for respiratory viruses, 208 reverse, for IgM, 128 for rotavirus, 288 for RSV, 218 Immunoblasts, in hantavirus infections, 645–646 Immunoblotting, see Western blotting (immunoblotting) Immunochromatography, 94–95 definition of, 89 for hantaviruses, 648 quality control in, 99–100 reporting results for, 99–100 for viral antibody detection, 99 for viral antigen detection, 95–99 Immunodeficiency, see also HIV (human immunodeficiency virus) infections infections in BKV, 421 CMV, 456–457 enterovirus, 268, 270 HHV-6, 498–499 HHV-7, 504 HMPV, 219 HSV, 434 measles virus, 563 parvovirus B19, 549–551 polyomavirus, 419–421 respiratory virus, 206–207 rotavirus, 285 RSV, 217 VZV, 465 Immunoelectron microscopy, 64, 71–73 of astroviruses, 293 of calicivirus, 291 U of rotaviruses, 288 Immunoenzymatic methods, see Immunohistochemistry (ICH) Immunofluorescence assay, 77–88 for adenovirus, 228 applications of, 78–81 for arboviruses, 390–392 for arenaviruses, 648 direct specimen testing, 78–79, 81–82 fixation in, 80–81 for HHV-8, 508–509 history of, 77 for HMPV, 218 for HSV, 440–441 IgM, 127–128 indirect, 81–82 for influenza virus, 213 for measles virus, 566 microscope for, 77–78 nasopharyngeal specimens in, 80 practical details of, 81–82 principles of, 77 quality assurance and quality control for, 82, 84 for rabies virus, 370–372 recent advances in, 84 for respiratory viruses, 207–208 for rheumatoid arthritis, 375 for RSV, 218 shell vial assay in, 80 slide preparation for, 80 specimen collection and processing for, 80 standard culture, 79–80 transport media for, 80 troubleshooting in, 82–83 Immunoglobulin(s) for CMV infections, 460 for HBV infections, 333 intravenous for enterovirus infections, 270 for parvovirus B19 infections, 554 for RSV infections, 217 for rabies virus infections, 377 for vaccinia virus infections, 538 for VZV infections, 468 Immunoglobulin A (IgA), antibodies to, enzyme immunoassay, 99 Immunoglobulin G (IgG) absorption of, in IgM determination, 126 determination of in CMV infections, 459 in HHV-6 infections, 502 Immunoglobulin M (IgM) antibodies to, enzyme immunoassay, 99 determination of, 124–133 chemical inactivation in, 124 in CMV infection, 459 in HAV infection, 317 in HDV infection, 349–350 in HHV-6 infection, 502 history of, 124 kits for, 130 physicochemical separation in, 124–126 recombinant protein-based assays in, 128–130 results interpretation in, 130 solid-phase immunologic detection in, 126–128 Immunogold electron microscopy, 72–73 G R V d e t i n 683 vip.persianss.ir 684 SUBJECT INDEX Immunohistochemistry (ICH), 103–109 antibody selection for, 104 applications of, 104–105 for arboviruses, 391 blocking in, 104 for cell culture, 105–106 for clinical specimens, 105 in CMV infections, 106 fixation in, 104 for HHV-8, 509 history of, 103–104 limitations of, 104 methods for, 104 in multiple antigen detection, 107 optimization of, 105 pretreatment antigen retrieval in, 104 quality control in, 105 for rabies virus, 371 results interpretation in, 105 in RNA virus infections, 106–107 stains for, 89–90 from tissue samples, 106 variables affecting performance, 104–105 Immunoperoxidase staining, 89–90, 440–441 Immunostaining, cell culture, 38 Immunotherapy, for EBV infections, 473 In situ hybridization (ISH) for HHV-8, 509 for HPV, 414 for parvovirus B19, 552–553 for VZV, 466 Inclusions in CMV infections, 53–54, 458 in urinary tract infections, 56–57 Incubation, see also specific viruses of cell cultures, 37–38 Indiana, virology services in, 666 Indirect binding assay, for HIV, 589–590 Indirect immunofluorescence, 81–82, 504 Infections, see individual viruses Infectious mononucleosis clinical features of, 470–471 diagnosis of, 472–473 epidemiology of, 470 immunochromatography for, 99 pathogenesis of, 469–470 specimen collection in, 22–23 treatment of, 473 virus causing, see Epstein-Barr virus (EBV) Infective dermatitis, HTLV-associated, 607 “Influenza” syndrome, 209 Influenza virus, 209–215 AI (avian), 205, 213–215 antigenic variability of, 209–210 biology of, 209–210 drug resistance in, 212 genera of, 209 Influenza virus infections, 209–215 avian, 205, 213–215 bacterial infections with, 211 chemoprophylaxis of, 215 clinical features of, 204, 209–211, 213–214 complications of, 210–211 diagnosis of, 208, 212–213, 215 cell culture, 38, 44, 47 electron microscopy, 68, 70 enzyme immunoassay, 95–99 hemadsorption test, 119 hemagglutination inhibition test, 120–122 immunofluorescence, 80, 84 membrane immunoassay, 93 neutralization test, 110 state laboratory services for, 666–667 epidemiology of, 204, 210, 213–214 flow cytometry in, 193 immunofluorescence for, 78 incubation period for, 214 natural history of, 210 prevention of, 215 specimen collection in, 20 susceptibility testing of, 134–135, 137–138, 143, 193 transmission of, 210 treatment of, 211–213, 215 vaccines for, 211–212, 215 Influenza-like syndrome, see Flu-like illness Inhalation, of viruses, 205–206 Inkoo virus, 395 INNO-LiPA HBV genotyping kit, 142 Inoculation, of cell cultures, 37–38 Insects, pathogens transmitted by, see Arbovirus(es) Interferon(s) for ATLL, 611 in HBV immune response, 330 for HBV infections, 333–334 for HCV infections, 342 in HSV immune response, 443 susceptibility testing of, 141–142 Interleukins, in HSV reactivation, 439 International AIDS Society, resistance-associated mutation database of, 140 International Organization for Standardization (ILO), Intravitam tests, for rabies virus, 373 Invader assay, 160 Ion-exchange chromatography, for IgM, 126 Iowa, virology services in, 666 Isla Vista virus, 642 Isolation, in cell cultures, see Cell cultures U G R V d e t i n K Kansas, virology services in, 666 Kaposi sarcoma-associated herpesvirus, see Human herpesvirus (HHV-8) Kaposi’s sarcoma, 504, 506–510 Kentucky, virology services in, 666 Keratitis cytopathology of, 60–62 HSV, 434 rubellla virus, 570 KI virus infections, 421 Kidney biopsy of, in BKV nephropathy, 420–421 BKV infections of, 179–180 transplantation of BKV nephropathy after, 420–421 HHV-6 infections after, 498–499 Kits for genotyping, 139–140, 142 for HCV, 345 for HIV, 588–591 for HMPV, 220 for IgM determination, 130 for influenza virus, 213 for measles virus, 563–564 quality assurance of, 9–11 for RSV, 218 for VZV, 467 for Western blotting, 154 Kobuvirus, 251, 295 Koplik spots, in measles virus infections, 562 Kunjin virus, see West Nile virus (WNV) J Jamestown Canyon virus, 395 Japanese encephalitis (JE) virus biology of, 394–395 susceptibility testing of, 190–191 vaccines for, 398 Japanese encephalitis (JE) virus infections diagnosis of, 190–191, 391, 392 epidemiology of, 397 Jaundice in HAV infections, 314 in HCV infections, 339 in HEV infections, 314 in YF virus infections, 397 JC virus (JCV) biology of, 417–419 discovery of, 417 JC virus (JCV) infections cancer in, 421 in pregnancy, 421 progressive multifocal leukoencephalopathy, 419–420 JE virus, see Japanese encephalitis (JE) virus Junin virus (JUNV), 643, 646 Junin virus (JUNV)infections diagnosis of, 648 pathogenesis of, 644 treatment of, 650 L La Crosse (LAC) encephalitis virus biology of, 395 history of, 388 La Crosse (LAC) encephalitis virus infections, 391 diagnosis of, 390, 392, 393 epidemiology of, 398 treatment of, 399 Laboratories design of, 14 reference, 14, 661–662 safety of, 14 staff competency and requirements for, 3–4 state, 663–671 Laboratory Response Network, 523, 663 LAC (La Crosse) encephalitis virus, see La Crosse (LAC) encephalitis virus Lagos bat virus, 364, 368 Lagovirus, 289 Laguna Negra virus, 643 Lamivudine for HBV infections, 333–334 susceptibility testing of, 139, 141–142 LANA protein, of HHV-8, 508–509 Larynx, papillomatosis of, 411–412 Lassa fever virus (LASV), 643 transmission of, 646 vaccines for, 650 Lassa fever virus (LASV) infections clinical features of, 644 diagnosis of, 648 epidemiology of, 646 pathogenesis of, 644–645 treatment of, 650 Latency in CMV infections, 458 in HIV infection, 588 vip.persianss.ir SUBJECT INDEX in HSV infections, 435–439 in VZV infections, 463–464 Latent cycle protein (LANA), of HHV-8, 508–509 Lateral flow immunoassay, see Immunochromatography Latex agglutination test, for rotaviruses, 287, 288 LCMV (lymphocytic choriomeningitis virus), see Lymphocytic choriomeningitis virus (LCMV) entries Lentiviruses, primate, 580–581, see also HIV; Simian immunodeficiency virus Leporipoxviruses, 528, 529 Leukemia, HTLV-associated, 604–605, 607, 611–612 Leukoencephalopathy, progressive multifocal, 419–420 Leukoplakia, oral, 471 LIA for HIV, 589–592 for HTLV, 609 LightCycler assay, 172 Line probe assay, in susceptibility testing, 139–140 Linearity, in nucleic acid assays, 176–177 Liquid array-based systems, 164–165 Liquid-based preparations, for cytology, 52 Liver biopsy of, in hepatitis, 327 cancer of, in hepatitis, 326 failure of, in HHV-6 infections, 500 hepatitis viruses affecting, see specific viruses, e.g., Hepatitis A virus (HAV) transplantation of for HBV infections, 334 for HCV infections, 342 HHV-6 infections after, 498–499 HHV-7 infections after, 504 Liver function tests in HAV infection, 314 in HBV infection, 326–327 in HCV infection, 326–327 in HDV infection, 326–327 in HEV infection, 314 Ljungan virus, 250 LMP antigens, 469–470 Loop-mediated isothermal amplification method, for mumps virus, 568 Louisiana, virology services in, 666 Lumbar dorsal root ganglia, HSV reactivation in, 437 Lymphadenopathy in ATLL, 605 in EBV infections, 471 in HHV-8 infections, 507 in HIV infection, 588 in monkey pox infections, 533 in rubella virus infections, 570 Lymphocytic choriomeningitis virus (LCMV), 643 animal models of, 641–642 immune response to, 644 transmission of, 646 Lymphocytic choriomeningitis virus (LCMV) infections epidemiology of, 646 pathogenesis of, 644–645 Lymphoma adult T-cell, 604–605, 611–612 Burkitt, 469, 471–472 in EBV infections, 471–472 Hodgkin’s, 472 HTLV-associated, 604–604, 607, 611–612 primary effusion, in HHV-8 infections, 508 Lymphopenia, in HIV infection, 586 Lymphoproliferative disease, EBV, 471–473 Lymphotropic herpesvirus, susceptibility testing of, 191–193 Lymphotropic herpesvirus infections, flow cytometry in, 191–193 Lyssaviruses, 364, 368; see also Rabies virus M MAC-ELISA, for arboviruses, 390, 391 Machupo virus (MACV), 643, 646 Machupo virus (MACV) infections clinical features of, 644–645 epidemiology of, 646 pathogenesis of, 644 Maine, virology services in, 666 Major histocompatibility complex, CMV interactions with, 458 Maraviroc, susceptibility testing of, 141 Maribavir, for CMV infections, 460–461 Maryland, virology services in, 666 Masks, for viral transmission interruption, 206 Massachusetts, virology services in, 666 Mayaro (MAY) virus, 394, 396 MCD, see Multicentric Castleman’s disease Measles virus, 562–566 biology of, 562 transmission of, 562 vaccines for, 562, 566 Measles virus infections atypical, 563 clinical features of, 562–563 complications of, 563 cytopathology of, 53, 55, 57, 61–62 diagnosis of, 563–566 cell culture, 44, 565–566 hemagglutination inhibition test, 120, 122 immunofluorescence, 78, 80 immunohistochemistry, 106–107 overview of, 563 serologic, 563–565 specimen collection for, 21, 23 viral antigen detection, 565–566 epidemiology of, 562, 566 prevention of, 566 Membrane enzyme immunoassays, 93 Meningitis enterovirus, 257–258 HSV, 434 mumps virus, 567 Mercaptans, in IgM determination, 124 Meridian methods, for antigen detection, 97 Michigan, virology services in, 666 Microarrays, 164–165 Microimmunofluorescence test, 635–636 Microscopy electron, see Electron microscopy fluorescence, see Immunofluorescence assay Microsphere immunoassays, for arboviruses, 390 MIF (microimmunofluorescence) test, for chlamydiae, 635–636 Milker’s nodule (pseudocowpox virus infection), 524, 527, 536–537 Minnesota, virology services in, 666 U Minor groove binding probes, 172 Mississippi, virology services in, 666 Missouri, virology services in, 666 Mitoxantrone, for ATLL, 611 MMR (measles, mumps, rubella) vaccine, 562, 569, 571–572 Mokola virus, 364 Molecular beacons, 164, 172 Molecular testing quality control, 12–13 quantitative, see Quantitative molecular techniques specimens for, 19–25 validation of, 8–9 Molluscum contagiosum virus biology of, 528–531 cytopathology, 60–61 replication of, 529–530 Molluscum contagiosum virus infections, 535–536 diagnosis of, 68, 69, 524–528, 535–536 differential diagnosis of, 536 epidemiology of, 535 pathogenesis of, 535 treatment of, 537–538 Monkeypox virus infections clinical features of, 532, 533 diagnosis of, 524–526, 534 differential diagnosis of, 534–535 epidemiology of, 533 pathogenesis of, 532–533 Monoclonal antibody(ies) HHV-7, 504 in immunofluorescence, 78–79, 81–82, 85 in neutralization test, 112–113 Monoclonal antibody pools, shell vial technique, 43 Monogram Biosciences genotyping assay, 140 Montana, virology services in, 666 Mosquitoes, pathogens transmitted by, see Arbovirus(es) Mouse inoculation test, for rabies virus, 371–372 Mouse mammary tumor virus, 579 MPV, see Human metapneumovirus (HMPV) Muleshow hantavirus, 641 Multicentric Castleman’s disease, in HHV-8 infections, 508 Multiparametric analysis, in flow cytometry, 197 Multiple myeloma, HHV-8 infections and, 508 Multiple sclerosis, HHV-6 and, 497, 500 Multiplex molecular assays, validation of, Mumps virus, 567–569 biology of, 567 discovery of, 567 transmission of, 567 vaccine for, 562, 568–569 Mumps virus infections clinical features of, 567 diagnosis of, 567–569 cell culture, 44 electron microscopy, 71 hemadsorption test, 119 hemagglutination inhibition test, 120 IgM assay, 128 immunofluorescence, 78, 80 specimen collection for, 23, 28 epidemiology of, 567, 569 prevention of, 569 G R V d e t i n 685 vip.persianss.ir 686 SUBJECT INDEX Murray Valley encephalitis (MVE) virus biology of, 394–395 susceptibility testing of, 190–191 Murray Valley encephalitis (MVE) virus infections, diagnosis of, 190–191, 390–392 Myalgia in influenza virus infections, 209 in SARS-CoV infections, 226 Mycoplasma hyorrhinis, electron microscopy of, 70 Myelitis, see also Poliomyelitis HSV, 434 in nonpoliovirus infections, 257 Myelodysplasia, in HHV-6 infections, 500 Myelodysplastic syndrome, HTLVassociated, 607 Myelopathy, HTLV-associated, 605–606 Myocarditis enterovirus, 259 hantavirus, 645 HHV-6, 499 N Nasal swabs or washing, 20, 26 NASBA, see Nucleic acid sequence-based amplification (NASBA) Nasopharyngeal carcinoma, in EBV infections, 471–472 Nasopharyngeal swabs or washing, 20–21, 26, 80 National Center for Human Immunodeficiency Virus (HIV)/AIDS, Viral Hepatitis, Sexually Transmitted Disease, and Tuberculosis Prevention (NCHHSTP), 661–662 National Center for Immunization and Respiratory Diseases (NCIRD), 661–662 National Center for Preparedness, Detection, and Control of Infectious Diseases (NCPDCID), 661–662 National Center for Zoonotic, Vector-borne, and Enteric Diseases (NCZVED), 661–662 National Respiratory and Enteric Virus Surveillance System (NREVSS), 205 NATs, see Nucleic acid amplification NCHHSTP (National Center for Human Immunodeficiency Virus (HIV)/ AIDS, Viral Hepatitis, Sexually Transmitted Disease, and Tuberculosis Prevention), 661–662 NCIRD (National Center for Immunization and Respiratory Diseases), 661–662 NCPDCID (National Center for Preparedness, Detection, and Control of Infectious Diseases), 661–662 NCZVED (National Center for Zoonotic, Vector-borne, and Enteric Diseases), 661–662 Nebraska, virology services in, 666 Needlestick injury, HIV infection risks in, 579 Negative staining methods, in electron microscopy, 65–67 Negri bodies, in rabies virus, 371 Neonatal infections CMV, 456, 460 enterovirus, 259–260 HBV, 333 HSV, 433, 435 parvovirus B19, 549, 553–554 rubella virus, 570–571 VZV, 465 Nephropathy, BKV-associated, 179–180, 420–421 Neuraminidase, 209 Neuraminidase inhibition assay, 138 Neurologic disorders, in influenza virus infections, 211 Neutralization test, 110–118 for astroviruses, 293 constant antiserum, varying virus format, 114 constant virus, 114 for enteroviruses, 265–267 hyperimmune antisera in, 117 innovations in, 110 materials for, 110–114 in multiple serotypes, 114–117 for mumps virus, 568 principles of, 110 procedures for, 114–117 for rabies virus, 374–375 for rotaviruses, 288 Neutropenia, in parvovirus B19 infections, 548 Nevada, virology services in, 666 Nevirapine, susceptibility testing of, 139 New Hampshire, virology services in, 666 New Jersey, virology services in, 666 New Mexico, virology services in, 666 New York, virology services in, 666 New York virus, 643 Newbury agent, 289 Newcastle disease virus, 119 Norovirus(es) biology of, 289 vaccines for, 291–393 Norovirus infections clinical features of, 289–290 diagnosis of, 291 electron microscopy, 68, 71 specimen collection for, 24 state laboratory services for, 666–667 epidemiology of, 290 pathophysiology of, 290 Norovirus-like particles, electron microscopy of, 71–72 North Carolina, virology services in, 666 North Dakota, virology services in, 666 Northern blotting, 150 Norwalk virus infections, 24 Norwalk-like virus, 65 NREVSS (National Respiratory and Enteric Virus Surveillance System), 205 Nucleic acid amplification, 156–168 for adenovirus, 228 for arboviruses, 392, 393 bDNA assay, 162, 174–176 for chlamydiae, 634–635 Cleavase Invader assay, 160 for CMV, 459–460 EIA-based, 160–162 FRET system, 163, 171 for HIV, 593 for HMPV, 220 for HSV, 441–442 hybrid capture, 162, 176 U G R V d e t i n hybridization probes, 163–164 hybridization protection assay, 162 hydrolysis (TaqMan) probes, 163, 171–172 for influenza virus, 213, 215 liquid array-based systems, 164–165 molecular beacons, 164, 172 for mumps virus, 568 for parainfluenza virus, 222 for parvovirus B19, 552–553 PCR, see PCR (polymerase chain reaction) for respiratory viruses, 208–209 for rhinovirus, 224 for RSV, 218 for SARS-CoV, 226 scorpion probes, 164 selection of system, 165 sequence-based (NASBA), 158–159, 173–174, 393 signal, 160 solid array-based systems, 164–165 state laboratory services for, 666–667 strand displacement (SDA), 159–160 strengths of, 156 SYBR green stain, 162–163, 171 transcription-mediated (TMA), 158–159 types of, 156 weaknesses of, 156 Nucleic acid sequence-based amplification (NASBA), 158–159, 173–174 for arboviruses, 393 for HIV, 594 NucliSENS EasyQ test, 594, 595 NucliSens HIV-1 QT assay, 173 NV-F virus, 355 O Ockelbo virus infections, diagnosis of, 392 Ocular infections Chlamydia trachomatis (trachoma), 630–632, 636 CMV, 456 corneal, 25, 28, 60–62 cytopathology, 60–62 HTLV, 607 specimen collections in, 25, 28 VZV, 465 Ohio, virology services in, 666 Oklahoma, virology services in, 666 Oncolytic viruses, as gene therapy vector, 446–447 O’nyong nyong (ONN) virus, 394, 396 OpenGene DNA sequencing system, 139–140 Opportunistic infections in ATLL, 605 in HIV infection, 588, 612 Optical immunoassays, 93–94 for chlamydiae, 635 for viral antigen detection, 95–99 Oral cavity, warts of, 412 Oral hairy leukoplakia, 471 OraQuick instruments, 94–95 Oregon, virology services in, 666 Orf virus infections, 524, 536–538 Oropouche (ORO) virus infections, 398 Ortho Cytoron absolute analytical flow cytometer, 189 Orthopoxvirus(es), 531–535 in animals, 529 biology of, 528–531 vip.persianss.ir SUBJECT INDEX genera of, 530 history of, 523 Orthopoxvirus infections diagnosis of, 523–528, 533 epidemiology of, 533 future outbreaks of, 539 pathogenesis of, 532–533 treatment of, 538–539 Oseltamivir for influenza virus infections, 212, 215 susceptibility testing of, 137–138 Otitis media adenovirus, 227–228 CoVs, 225 HMPV, 219 rhinovirus, 223 RSV, 216 Oxytetracycline, for chlamydial infections, 636 P p24 antigen test, for HIV, 593 Pain chest, in enterovirus infections, 259 in rabies virus infection, 366 in zoster, 465 Paired samples, 100 Palivizumab, for RSV infections, 217–218 Pandemics influenza virus, 209, 210 SARS-CoV, 225–226 Papanicolaou stain, modified, 52–53 Papilloma(s), genital, 409, 411, 414 Papillomatosis, recurrent respiratory, 411–412 Papillomaviruses, 71; see also Human papillomavirus virus (HPV) Papovaviruses, 69, 71 Parainfluenza virus, 220–222 biology of, 220 genera of, 220 immune response to, 221 Parainfluenza virus infections, 220–222 clinical features of, 204, 220–222 cytopathology of, 53–55 diagnosis of, 208, 222 cell culture, 38, 41, 44, 47 electron microscopy, 70 enzyme immunoassay, 95 hemadsorption test, 119 hemagglutination inhibition test, 120–122 immunofluorescence, 78–80 transmission of, 220–221 types of, 220–221 vaccines for, 222 in elderly persons, 221 epidemiology of, 205, 220, 222 recurrent, 221 treatment of, 222 Paralysis in enterovirus infections, 259 in nonpoliovirus infections, 257 in poliomyelitis, 256–257 in rabies virus infection, 366 Paramyxoviruses, 204; see also specific viruses electron microscopy of, 68, 71 Paraparesis, HTLV-associated, 605–606 Parapoxvirus infections, 536–538 diagnosis of, 68, 524–528, 537–538 epidemiology of, 537 pathogenesis of, 536–537 treatment of, 537–538 Parapoxviruses, 528–531 Paresthesia, in rabies virus infection, 366 Parotitis, in mumps virus infections, 567 Particle agglutination assay for HIV, 591 for HTLV, 608–609 Parvovirus(es), 204; see also specific viruses discovery of, 546 types of, 546 Parvovirus B19 infections, 546–554 clinical features of, 548–550 diagnosis of, 548–553 cell culture, 549 electron microscopy, 551–552 IgM assay, 128 immunoassay, 552 nucleic acid techniques, 552–553 PCR, 553 specimen collection for, 25, 548–549 pathogenesis of, 547–548 in pregnancy, 549, 553–554 prevention of, 553 treatment of, 553–554 Paul-Bunnell test, for EBV, 472 PCR (polymerase chain reaction) for arboviruses, 392 for arenaviruses, 648 for astroviruses, 293 for caliciviruses, 291 for chlamydiae, 635 for CMV, 459–460 description of, 156–158 for EBV, 473 for enteroviruses, 265–266 for GBV-C, 352 for HCV, 344 for HEV, 317 for HHV-6, 501–502 for HHV-7, 504 for HHV-8, 509 history of, 169–170 for HIV, 593–595 for HPeV, 267 for HPV, 413–414 for HSV, 441–442 for HTLV, 609–611 for measles virus, 566 for mumps virus, 568 for parvovirus B19, 553 for poxviruses, 527–528 for rabies virus, 372–373 real-time, 171–173 for rotavirus, 288 RT (reverse transcriptase), 171 in susceptibility testing, 139 for TTV infections, 354–355 for VZV, 466 Pediatric infections, see also Congenital infections; Neonatal infections astrovirus, 292–293 chlamydial, 632, 636 CMV, 456 CoV, 225 EBV, 470–471 enterovirus, 259–260 HBV, 333 HHV-6, 497–498 HHV-7, 503–504 HIV, 588, 598 HMPV, 218–220 HSV, 431, 433, 435 U HTLV, 608 influenza virus, 210–211 norovirus, 290 parainfluenza virus, 220–222 parvovirus B19, 548–549, 553–554 polyomavirus, 419 respiratory virus, 206 rhinovirus, 222–223 rotavirus, 285 RSV, 215–218 sapovirus, 290 VZV, 465 PEL, see Primary effusion lymphoma Pelvic inflammatory disease, 631–632 Penciclovir, susceptibility testing of, 135, 138, 143 Pennsylvania, virology services in, 666 Pericarditis, enterovirus, 259 PERT (product-enhanced RT) assays, 595–596 Pertussis-like syndrome, adenovirus, 228 Phagocytosis, of Chlamydia, 631 Pharyngitis adenovirus, 227 EBV, 471 HSV, 433 HBoV, 229 influenza virus, 209 parainfluenza virus, 221 Pharyngoconjunctival fever, 227 PhenoSense assays, 138, 140 Phenotypic assays, in antiviral susceptibility testing, 135–136, 138–139 Phosphonoformic acid, for HHV-7 infections, 504 Phosphotungstic acid, electron microscopy of, 66 Phycoerythrin, 78 Physicochemical separation methods, for IgM, 124–126 Picornaviruses, 249–250, 294; see also specific viruses Plantar warts, 409, 410 Plaque assay, 111 Plaque autoradiography, 138 Plaque reduction assay, in susceptibility testing, 136, 137 Plaque-forming units, 111 Plaque-reduction neutralization test for arboviruses, 389 for measles virus, 565 Pleconaril, for enterovirus infections, 268 Pleurodynia, in enterovirus infections, 259 PML, see Progressive multifocal leukoencephalopathy Pneumonia adenovirus, 228 Chlamydia pneumoniae, 632 Chlamydia psittaci, 632–633 Chlamydia trachomatis, 632 CoVs, 225 cytopathology of, 53–55 enterovirus, 260 HMPV, 219–220 HTLV, 607 influenza virus, 211, 212, 214 measles virus, 563 parainfluenza virus, 220–222 rhinovirus, 223 RSV, 216 SARS-CoV, 226 viruses causing, 204 G R V d e t i n 687 vip.persianss.ir 688 SUBJECT INDEX Pneumonitis, HSV, 434 Pneumoviruses, 204; see also specific viruses Poliomyelitis bulbar, 257 clinical features of, 255–257 eradication of, 268–269 postpolio syndrome after, 257 Poliovirus classification of, 250 cytopathic effects of, 256 discovery of, 249 immune response to, 260 morphology of, 252 neutralization of, 253 replication of, 254 transmission of, 261 vaccines for, 249, 267–269 Poliovirus infections, see also Poliomyelitis diagnosis of, 44, 255, 265 epidemiology of, 262–264 incubation period for, 255 Polyomavirus(es), 230, 417–423 biology of, 417–419 transmission of, 205 Polyomavirus infections BK virus nephropathy, 420–421 cancer, 421 hemorrhagic cystitis, 421 pathogenesis of, 419–421 in pregnancy, 421 in primary immunodeficiency, 421 progressive multifocal leukoencephalopathy, 419–420 respiratory, 230, 421 treatment of, 421 Postherpetic neuralgia, 465 Postpolio syndrome, 257 Posttransplant lymphoproliferative disease, 471–473 Powassan (POW) virus, 394–395 Powassan (POW) virus infections diagnosis of, 392 epidemiology of, 393 Poxvirus(es), 523–545 classification of, 528 immune response to, 530–531 life cycle of, 529–531 molluscum contagiosum virus, see Molluscum contagiosum virus morphology of, 528–529 orthopoxviruses, 523–524, 526, 530–535, 538 parapoxviruses, 524–531, 536–538 replication of, 529–531 taxonomy of, 528 transmission of, 530 yatapoxviruses, 524–531, 537–538 Poxvirus infections biology of, 528–531 diagnosis of, 523–528 cell culture, 524–526 DNA analysis, 527–528 electron microscopy, 526 future, 528 histology, 526 method evaluation, 528 serology, 526–527 specimen handling for, 523–524 future outbreaks of, 539 prevention of, 538–539 treatment of, 538–539 Precision, of nucleic acid assays, 177 Prednisolone, for ATLL, 611 Prednisone, for parvovirus B19 infections, 553 Pregnancy, infections in BKV, 421 HBV, 333 HCV, 341 HEV, 320 HTLV, 608 influenza virus, 211 JCV, 421 LCMV, 645 measles virus, 563 parvovirus B19, 549, 553–554 rubella virus, 570–571 Primary effusion lymphoma, in HHV-8 infections, 508 Primate T-cell lymphotropic viruses (PTLVs), 578, 601 Primer Express design software, 157 PRNT (plaque-reduction neutralization test) for arboviruses, 389 for measles virus, 565 Probes hybridization, 163–164 hydrolysis, 163 minor groove binding, 172 scorpion, 164 Procedure manual, Product-enhanced RT assays, 595–596 Proficiency testing, 5–6, 370–371 Progressive multifocal leukoencephalopathy, 419–420 Progressive rubella panencephalitis, 570 Prospect Hill virus, 642 Protein A, gold-labeled, immunoelectron microscopy, 72–73 Pseudocowpox virus infections, 524, 527, 536–537 Pseudoreplica approach, in electron microscopy, 67–68 Pseudoviruses, in neutralization test, 112 Psittacosis, 631–636 PTLVs, see Primate T-cell lymphotropic viruses Public health laboratories federal, 661–662 state, 663–671 Puumala virus (PUUV), 642, 643 transmission of, 647 vaccines for, 650 Puumala virus (PUUV) infections diagnosis of, 648 epidemiology of, 648 treatment of, 650 U G R V d e t i n regulatory requirements, staff competency, 3–4 troubleshooting in, Quality control, cell culture, 11–12 enzyme immunoassays, 99–100 failure of, immunochromatography, 99–100 immunofluorescence, 82, 84 immunohistochemistry, 105 molecular testing, 12–13 optical immunoassays, 99–100 Quantitative molecular techniques, 169–184 advantages of, 180 applications of, 177–180 bDNA assay, 162, 174–176 for BKV, 179–180 for CMV, 170, 178–179 disadvantages of, 180 for EBV, 179 for HBV, 178 for HCV, 170, 176, 178 for HHVs, 179 history of, 169–170 for HIV, 170, 174, 177–178 hybrid capture assay, 160–162, 176 information resources for, 169 NASBA (nucleic acid sequence-based amplification), 158–159, 173–174, 393 PCR, see PCR (polymerase chain reaction) performance issues, 176–177 tips for, 180 Quantitative reporting, for enzyme immunoassays, 99–100 Quick Vue Flu A & B, 98 Quidel methods, for antigen detection, 98 Q Qualitative reporting, of enzyme immunoassays, 99 Quality assurance, 3–17 in analytical phase, 7–13 comprehensive, 14 continuous quality improvement, 14 documentation for, 4, 9, 15 immunofluorescence, 82, 84 importance, laboratory design, 14 oversight, 14–15 in postanalytical phase, 13–14 in preanalytical phase, procedure manual, proficiency testing, 5–6 reference laboratories, 14 R Rabbit disease virus, 289 Rabbit endogenous retrovirus, 578 Rabies fluorescent focus inhibition test, 375 Rabies virus, 363–386 antibodies to, 374–375 biology of, 364, 395 carriers of, 366 history of, 363–364 immune response to, 365 postexposure treatment for, 364, 368, 375–376, 378 transmission of, 363, 365 vaccines for, 375–379 variants of, 367, 374 Rabies virus infections in animals control of, 375–379 diagnosis of, 369–373 epizootiology of, 366–367 history of, 363–364 pathogenesis of, 365–366 clinical features of, 366 control of, 375–379 diagnosis of, 367–375 in animals, 369–373 in humans, 373–375 immunofluorescence, 78 immunohistochemistry, 107 isolation techniques, 371–372 neutralization test, 110 state laboratory services for, 666–667 vip.persianss.ir SUBJECT INDEX epidemiology of, 367 incubation period for, 366 pathogenesis and pathology of, 365–366 prodromal stage of, 366 specimen collection in, 23 survival in, 366 treatment of, 373 Radioimmunoassays, for parvovirus B19, 552 Ranimustine, for ATLL, 611 Rapid, point-of-care tests for HAV infection, 318 for HEV infection, 318 Rash in enterovirus infections, 259 in HHV-6 infections, 497 in HIV infection, 588 in measles virus infections, 562–563 in parvovirus B19 infections, 547–548 in rubella virus infections, 569–570 Reagents, quality assurance, 9–11, 13 Receptors, viral, flow cytometric detection of, 197 Recombinant virus assays, 128–130, 138–139 Recoviruses, 289 Rectal mucosa, HIV penetration of, 585 Rectal swabs, 21 Recurrent respiratory papillomatosis, 411–412 Red cell suspensions, standardization of, 11 Reference laboratories, 14, 661–662 Remel methods, for antigen detection, 97 Reoviruses biology of, 394 electron microscopy of, 66, 68 hemagglutination inhibition test for, 120, 122 Replicative cycle, 425–431; see also specific viruses, replication of and biology of Reports, 13–14, 99–100 Resistance, antiviral, see Antiviral drugs, resistance to Respiratory syncytial virus (RSV), 215–218 biology of, 215–216 HMPV comparison with, 218–219 immune response to, 217 subgroups of, 216 transmission of, 216 vaccines for, 217 Respiratory syncytial virus (RSV) infections, 215–218 clinical features of, 204, 216–217 complications of, 216–217 cytopathology of, 53–55 diagnosis of, 208, 218 cell culture, 44, 47 electron microscopy, 68, 70 enzyme immunoassay, 95–99 immunofluorescence, 78, 79–80 immunohistochemistry, 106–107 membrane immunoassay, 93 specimen collection for, 20, 21 epidemiology of, 204, 215 extrapulmonary, 216 immunity to, 217 in immunodeficiency, 217 pathogenesis of, 216 prevention of, 217–218 recurrent, 217 treatment of, 217–218 Respiratory tract infections clinical features of, 203–204 coinfections with, 203–204 cytopathology of, 53–56 diagnosis of, 207–230 electron microscopy, 67–68, 71 specimen collection for, 19–20, 26, 28 economic impact of, 203 enterovirus, 260 epidemiology of, 204–207, 209–230 geographic distribution of, 204–205 populations susceptible to, 206–207 prevention of, 206, 209–230 seasonality of, 204–205 treatment of, 209–230 viruses causing, see Respiratory viruses; specific viruses Respiratory viruses, 203–248; see also specific viruses adenovirus, 227–229 “classic,” 203 classification of, 203 clinical syndromes due to, 203–204 CoVs, 224–227 diagnostic methods for, 207–209 HBoV, 229–230 HMPV, 218–220 influenza virus, 209–215 newly described, 203 parainfluenza virus, 220–222 polyomavirus, 230, 421 rhinovirus, 222–224 RSV, 215–218 taxonomy of, 204 transmission of, 205–206 tropism of, 203–204 Respiroviruses, 220 Restriction endonuclease fragment length polymorphism, for poxviruses, 527 Reticulocytes, destruction of, in parvovirus B19 infections, 548 Retroviruses, see also HIV; Human T-cell lymphotropic virus; Simian immunodeficiency virus types of, 578 Reverse immunoassays, for IgM, 128 Reverse transcriptase, HIV assays for, 595–596 functions of, 582 transcription errors related to, 584 Rex proteins, HTLV, 601–602 Rhabdoviruses, 394, 395, 398 Rheumatoid arthritis, parvovirus B19 infections and, 550 Rheumatoid factor, in IgM determination, 127 Rhinitis HBoV, 229 HMPV, 219 HSV, 434 parainfluenza virus, 221 Rhinovirus(es), 222–224 biology of, 222–223 classification of, 223–224 immune response to, 223 transmission of, 223 Rhinovirus infections clinical features of, 204, 223 coinfections with, 223 diagnosis of, 223–224 cell culture, 44, 47 neutralization test, 114–117 epidemiology of, 205, 223 incubation period of, 223 treatment of, 224 Rhode Island, virology services in, 667 U Ribavirin for arenavirus infections, 650 for hantavirus infections, 650 for HCV infections, 342 for HMPV infections, 220 for LAC encephalitis virus infections, 399 for parainfluenza virus infections, 222 for RSV infections, 217 Rift Valley fever virus biology of, 395 epidemiology of, 398 immunohistochemistry for, 107 Rimantadine for influenza virus infections, 212 susceptibility testing of, 134, 137 Rituximab, for EBV infections, 473 R-mix, cell cultures, 44 RNA viruses, see also specific viruses immunohistochemistry for, 106–107 Rodent-borne virus(es), 641–657 biology of, 642–644 overview of, 641–642 Rodent-borne virus infections diagnosis of, 648–649 epidemiology of, 646–648 pathogenesis of, 644–646 prevention of, 650 treatment of, 649–650 Roseola HHV-6, 494, 496–498, 500–501 HHV-7, 503–504 Roseoloviruses, see Human herpesvirus 6; Human herpesvirus Ross River (RR) virus, 392, 394, 396 Rotavirus(es), 283–288 biology of, 283–284 immune response to, 287 transmission of, 287 vaccines for, 288 Rotavirus infections clinical features of, 284–286 diagnosis of, 287–288 cell culture, 44 electron microscopy, 66, 68, 71, 72 enzyme immunoassay, 98 immunohistochemistry, 107 specimen collection for, 24 epidemiology of, 287 pathogenesis of, 286–287 treatment of, 287–288 RR (Ross River) virus, 392, 394, 396 RSV, see Respiratory syncytial virus (RSV) RSV/ICR method, 97 Rubella virus, 569–572 biology of, 569–570 discovery of, 569 immune response to, 570 prevention of, 571–572 vaccines for, 569, 571–572 Rubella virus infections clinical features of, 569–570 congenital, 570–571 diagnosis of, 570–571 electron microscopy, 68, 70, 71 hemagglutination inhibition test, 122 IgM determination, 125 immunofluorescence, 80 specimen collection for, 21, 25 discovery of, 569 epidemiology of, 569 Rubeola virus, see Measles virus Rublaviruses, 220 G R V d e t i n 689 vip.persianss.ir 690 SUBJECT INDEX S Sabia virus, 643 Safety, 14 for poxvirus transport, 523–524 for retrovirus handling, 578–579 St Louis encephalitis (SLE) virus biology of, 394–395 history of, 387 St Louis encephalitis (SLE) virus infections diagnosis of, 390–393 epidemiology of, 397 Saliva arenaviruses in, 641, 644, 647 hantaviruses in, 641, 644, 647 HHV-6 in, 495 HHV-7 in, 503 HHV-8 in, 506–507 HIV in, 591 HSV in, 432–433 mumps virus in, 567 rabies virus in, 373–374 rodent-borne viruses in, 641, 644, 647 Sapovirus, biology of, 289 Sapovirus infections clinical features of, 289 diagnosis of, 68 epidemiology of, 290 Sarcoma, Kaposi’s, 504, 506–510 SARS-CoV, see Severe acute respiratory syndrome coronavirus (SARS-CoV) SAS methods, for antigen detection, 98 Scorpion probes, 164 SDA, see Strand displacement amplification Sealpox virus infections, 536–537 Seizures in HHV-6 infections, 500 in rabies virus infections, 366 Semliki Forest virus, 394, 398 Seoul virus, 643, 650 Sequence analysis, for HCV, 345 Seroconversion, in HIV infection, 589, 591 Serology in arbovirus infections, 389–390 in chlamydial infections, 635–636 in CMV infections, 458–459 in EBV infections, 472 in enterovirus infections, 266–267 enzyme immunoassays for, see Enzyme immunoassays (EIAs) in hantavirus infections, 648 in HAV infections, 317–318 in HBV infections, 334–335 in HCV infections, 343 in HDV infections, 349–350 hemagglutination inhibition, 120–122 in HEV infections, 317–318 in HHV-6 infections, 502 in HHV-7 infections, 504 in HHV-8 infections, 508–509 in HPV infections, 414 in HSV infections, 442 in HTLV infections, 609 in mumps virus infections, 568 neutralization test, see Neutralization test in poxvirus infections, 526–527 in rotavirus infections, 288 in rubella virus infections, 571 state laboratory services for, 666–667 in VZV infections, 467 Serum, specimen collection from, 20–25 Severe acute respiratory syndrome coronavirus, see SARS-CoV Severe acute respiratory syndrome coronavirus (SARS-CoV), 225–227 biology of, 226 transmission of, 205 Severe acute respiratory syndrome coronavirus (SARS-CoV) infections, 225–227 case definition of, 226 clinical features of, 226 diagnosis of, 208, 226 electron microscopy, 73–74 IgM assay, 128 specimen collection for, 20, 26 epidemiology of, 225–226 HMPV infections with, 219 treatment of, 226–227 Shell vial (centrifugation) technique, 39–45 description of, 39–40 equipment for, 42 immunofluorescence confirmation in, 80 mixed-cell cultures in, 43 monoclonal antibody pools in, 43 procedure for, 42–43 for respiratory viruses, 208 sensitivity of, 40 Shingles (herpes zoster), 464–465, 469; see also Varicella-zoster virus Shock, in dengue virus infections, 387, 397 Shope fibroma virus, 529 Signal amplification methods, 160 Simian immunodeficiency virus (SIV) biology of, 580–581 discovery of, 578 immune response to, 586 Simian immunodeficiency virus (SIV) infections, pathogenesis of, 586 Simian T-cell lymphotropic retrovirus (STLV), 578, 601 Sin Nombre virus (SNV) transmission of, 646–647 vaccines for, 650 Sin Nombre virus (SNV) infections clinical features of, 645 treatment of, 650 Sindbis virus, 394 Sinusitis Chlamydia pneumoniae, 632 HTLV, 607 SIV, see Simian immunodeficiency virus entries Sixth disease, 494 Skin biopsy of, in rabies virus infections, 373–374 electron microscopy of, 68 HSV infections of, 433–439 lesions of, in ATLL, 605 parvovirus B19 infections in, 548–550 poxvirus infections of, 531–538 swabs from, 21, 23, 25–27 VZV infections of, 565 warts on, 408–410, 414 “Slapped cheek” rash, in parvovirus B19 infections, 548 SLE virus, see St Louis encephalitis (SLE) virus Slides, preparation from swabs, 80 Smallpox diagnosis of, 523–528, 534 eradication of, 531–532 U G R V d e t i n future reintroduction of, 539 history of, 523 recovery from, 531 as terrorist weapon, 539 transmission of, 532–533 vaccines for, 539 virus causing, see Variola virus Smears, cytology, 52 Snowshoe hare (SSH) virus, biology of, 395 SNV, see Sin Nombre virus entries Solid array-based systems, 164–165 Solid-phase techniques enzyme immunoassay, 90–91 for IgM detection, 126–128 South Carolina, virology services in, 667 South Dakota, virology services in, 667 Southern blotting, 150 Spanish flu of 1918, 210 Specificity, of nucleic acid assays, 177 Specimen(s) for reference testing, 661 for state health departments, 661, 664 Specimen collection blood, 27 brain tissue, for rabies virus, 369–370 for cell cultures, 37 central nervous system, 21–23, 27–28, 369–371 cerebrospinal fluid, 21–25, 27–28 dermal, 21, 23, 25–27 fecal, 28 gastrointestinal, 24, 28 genital, 24 for HIV, 591 for immunofluorescence assay, 80 ocular, 25, 28 for poxviruses, 523–524 quality assurance in, for reference testing, 661 rejection in, respiratory, 19–20, 26, 28, 207–208 urine, 28 Specimen requirements, 18–35 collection, see Specimen collection selection, 18–19 storage, 28–29 transport, 28–29 Specimen selection, 18–19 Specimen transport, 28–29 for poxvirus diagnosis, 523–524 for rabies virus diagnosis, 369, 374 Spinal cord HTLV infections of, 605–606 poliovirus infection of, see Poliomyelitis Spindle cells, in Kaposi’s sarcoma, 507 Splenomegaly, in EBV infections, 471 “Spot” test, for EBV, 472 Sputum, specimen collection from, 26 SSH (snowshoe hare) virus, 395 SSPE (subacute sclerosing panencephalitis), 563 Staff, competency and requirements for, 3–4 Staining for chlamydiae, 633–634 cytopathology, 52–53 immunofluorescence, 81–82 immunohistochemical, 89–90 Staphylococcus aureus, in IgM determination, 126 State health departments, specimen submission to, 661, 664 Stavudine, susceptibility testing of, 138 vip.persianss.ir SUBJECT INDEX Stem cell transplantation, HHV-6 infections after, 498–499 STLV, see Simian T-cell lymphotropic retrovirus Stool specimens collection of, 28 electron microscopy of, 68–69, 71 for rotavirus, 287 Strand displacement amplification (SDA), 159–160, 635 Streptococcal protein G, in IgM determination, 126 Strip immunoblot assay, for hantaviruses, 648 Subacute sclerosing panencephalitis (SSPE), 563 Sucrose density gradient centrifugation, in IgM determination, 124–125 Suipoxviruses, 528, 529 Super E-mix, for cell cultures, 44, 45 Superinfections, HDV, 348–349 Susceptibility testing, see Antiviral susceptibility testing Swabs, 28–29 dermal, 21, 23, 25–27 genital, 21, 24 nasal, 20, 26 nasopharyngeal, 20–21, 26 rectal, 21 slide preparation from, 80 throat, 20–25 SYBR green I system, 162–163, 171 T T lymphocytes, involvement in infections Chlamydia, 631 CMV, 457–458 EBV, 473 HIV, 583–588 HTLV, 603–607, 611–612 rodent-borne viruses, 645–646 T-705 pyrazine derivative, for arenavirus infections, 650 Tacaribe virus, 643 Tamiami arenavirus, 641 Tanapox virus infections, 538 clinical features of, 535 diagnosis of, 524, 527, 535 TaqMan assays, 163, 171–172 for arboviruses, 392–393 for mumps virus, 568 Target-specific extension products, 165 Tax proteins, HTLV, 601–604 TBE virus, see Tick-borne encephalitis (TBE) virus entries Telbivudine for HBV infections, 333 susceptibility testing of, 141, 142 Temporal medial lobe epilepsy, in HHV-6 infections, 500 Tennessee, virology services in, 667 Tetracycline, for chlamydial infections, 636 Texas, virology services in, 667 Thermo Electron methods, for antigen detection, 97 Three-day measles, see Rubella virus infections Throat swabs or washing, 20–25 Tick(s), pathogens transmitted by, see Arbovirus(es) Tick-borne encephalitis (TBE) virus, 392–395, 397 Tick-borne encephalitis (TBE) virus infections diagnosis of, 392, 393 epidemiology of, 397 Titration, in neutralization test, 111–113 TMA, see Transcription-mediated amplification Togaviruses, 122, 394 Tolerance limit, of nucleic acid assays, 177 Tonsillitis, adenovirus, 227 TORCH infections, 456 Toroviruses, 68, 294 Torovirus-like particles, electron microscopy of, 65 Torquetenomidivirus (TTMDV), 353–355 Torquetenominivirus (TTMV), 353–355 Torquetenovirus (TTV), 353–355 Tracheobronchitis, adenovirus, 228 Trachoma, 630 epidemiology of, 632 pathogenesis of, 631 treatment of, 636 Training requirements, Transcription, 426–428 Transcription-mediated amplification (TMA), 158–159 for chlamydiae, 635 for HIV, 594 Transmission, viral, 205–206; see also specific viruses, transmission of Transplantation, see also specific organs bone marrow, for ATLL, 611 infections after arenavirus, 644 BKV, 421 CMV, 456, 460, 461 EBV, 471 HHV-6, 498–499 HHV-7, 504 HMPV, 219 LCMV, 645 parainfluenza virus, 222 respiratory, 207 rhinovirus, 223 RSV, 217 kidney, BKV nephropathy after, 420–421 liver, for HBV infections, 334 lymphoproliferative disease after, 471–473 rabies virus transmission in, 365 Trigeminal ganglia, HSV reactivation in, 437 Tropical spastic paraparesis, HTLVassociated, 605–606 TrueGene HIV-1 genotyping kit, 139–140 TRUGENE HBV genotyping kit, 142 TTMDV (torquetenomidivirus), 353–355 TTMV (torquetenominivirus), 353–355 TTV (torquetenovirus), 353–355 Tube-based enzyme immunoassay, 90–91 Tula virus, 642 U Urinary tract infections, cytopathology, 56–57 Urine discolored in HAV infection, 314 in HEV infection, 314 specimens of collection of, 28 electron microscopy of, 71 Utah, virology services in, 667 Uveitis, HTLV-associated, 607 V Vaccines adenovirus, 228, 229 ANDV, 650 arboviruses, 398–399 Argentinian hemorrhagic fever, 650 DNA, 444 hantavirus, 650 HAV, 318–320 HBV, 333 HCV, 341–342 HHV-6 infections due to, 498 HMPV, 220 HPV, 414 HSV, 443–444 HTNV, 650 influenza virus, 211–212, 215 LASV, 650 live attenuated, 443–444 measles virus, 562, 566 MMR (measles, mumps, rubella), 562, 569, 571–572 mumps virus, 562, 568–569 parainfluenza virus, 222 poliovirus, 249, 267–269 PUUV, 650 rabies virus, 378–379 rotavirus, 288 RSV, 217 smallpox, 539 subunit, 443 therapeutic, 444 vaccinia virus, 539 VZV, 468–469 YF virus, 398 Vaccinia virus infections diagnosis of, 524, 525, 535 distribution of, 532 pathogenesis of, 533 treatment of, 538 vaccines for, 539 Vaccinia-like virus infections, 533 Valacyclovir for HSV infections, 444–445 for oral hairy leukoplakia, 471 for VZV infections, 467 Valgancyclovir, for CMV infections, 460 Validation, 7–9 Valproate, for ATLL, 611 Varicella-zoster virus (VZV), 462–469 biology of, 462–465 genome of, 462 history of, 462 immune response to, 464–465 incubation of, 465 latency of, 463–464 phenotypes of, 463 replication of, 462–464 susceptibility testing of, 134–138, 143 vaccines for, 468–469 G R V d e t i n 691 U Ultracentrifugation, in electron microscopy, 67–68 Ultraviolet light, for enterovirus inactivation, 253, 255 Uni-Gold Recombigen instruments, 94 Uranyl acetate, in electron microscopy, 66 Urethritis Chlamydia trachomatis, 631–632 HSV, 434 vip.persianss.ir 692 SUBJECT INDEX Varicella-zoster virus (VZV) infections clinical features of, 465 cytopathology of, 61 diagnosis of, 465–467 antigen detection, 467 cell culture, 38, 43, 45–46, 467 cytopathologic, 467 electron microscopy, 68, 69, 71, 73 immunofluorescence, 78, 79–80, 82 molecular, 467 serologic, 467 specimen collection for, 19, 21, 23, 26–27 epidemiology of, 465 prevention of, 468 treatment of, 467–468 Variola virus, see also Smallpox laboratory stocks of, 532 replication of, 529 specimen handling for, 523–524 transmission of, 532–533 vaccines for, 539 VCA (viral capsid antigen), EBV, 472 Venezuelan equine encephalitis (VEE) virus biology of, 394 history of, 388 vaccines for, 398 Venezuelan equine encephalitis (VEE) virus infections diagnosis of, 390, 391 epidemiology of, 395–396 Venezuelan hemorrhagic fever (VHF), 641, 646 Verification, 7–9 Vermont, virology services in, 667 Versant HIV-1 RNA test, 594 Versant HIV-1 RT resistance assay, 140 Vesicular exanthema of swine virus, 288 Vesicular stomatitis virus (VSV), 395, 398 Vesiviruses, 289 Vidarabine, susceptibility testing of, 137 VIDAS instrument, 93, 99 Vincristine, for ATLL, 611 Vindesine, for ATLL, 611 Viral antibody(ies), in immunohistochemistry, 104 Viral antibody detection enzyme immunoassay, 99 immunochromatography, 94–95, 99 paired samples in, 100 Viral antigen(s) drift and shift of, 209–210 EBV, 469–472 echoviruses, 251 enteroviruses, 251, 253 HBV, 327, 328, 330–332, 334–335 HCV, 344–345 HDV, 347, 350 HIV, 593 influenza, 209–210 retrieval of, in immunohistochemistry, 103–109 Viral antigen detection, see also Antigenemia test adenovirus, 228 CMV, 459 enzyme immunoassay, 95–99 HBV, 334–335 HDV, 350 HEV, 317–318 HMPV, 220 HPV, 413 HSV, 440–441 immunochromatography, 94–95 immunohistochemistry in, 103–109 influenza virus, 213 optical immunoassay, 95–99 paired samples in, 100 parainfluenza virus, 222 quality assurance for, 10–11 rabies virus, 370–371 respiratory, 208 rotavirus, 288 RSV, 218 VZV, 466 Viral capsid antigen (VCA), EBV, 472 Viral cytopathology, see Cytopathology, viral Viral infections, see individual viruses Viral isolation, see Cell cultures Viral load assays, 169; see also Quantitative molecular techniques for HIV, 169, 178, 599–600 Virginia, virology services in, 667 ViroSeq HIV-1 genotyping system, 139–140 Virtual Phenotype assay, 140 VP 63843, for enterovirus infections, 268 VSV (vesicular stomatitis virus), 395, 398 VZV, see Varicella-zoster virus (VZV) entries d e U G R V W Warts cutaneous, 408–410, 414 diagnosis of, 412–414 genital, 409, 411, 414 HIV genotypes in, 409 oral, 412 pathogenesis of, 408–409 transmission of, 409 treatment of, 414 Washington, virology services in, 667 Water enteroviruses in, 261 hepatitis viruses in, see Hepatitis A virus (HAV); Hepatitis E virus (HEV) Water drop method, for electron microscopy, 67 Weakness, in rabies virus infection, 366 WEE virus, see Western equine encephalitis (WEE) virus entries West Nile virus (WNV) biology of, 394–395 vaccines for, 399 West Nile virus (WNV) infections diagnosis of, 390, 392 flow cytometry, 190–191 IgM assay, 128 specimen collection for, 22 epidemiology of, 396–397 history of, 388 risk factors for, 393 West Virginia, virology services in, 667 t i n Western blotting (immunoblotting), 90, 150–155 advantages of, 154 for arenaviruses, 648 commercial kits for, 154 disadvantages of, 154 for hantaviruses, 648 for HHV-7, 504 history of, 150–151 for HIV, 589, 591–593, 596 for HSV, 442 for HTLV, 609–610 principles of, 150–152 procedure for, 152–153 Western equine encephalitis (WEE) virus biology of, 394 history of, 387 vaccines for, 398 Western equine encephalitis (WEE) virus infections diagnosis of, 390–393 epidemiology of, 396 Whitewater Arroyo virus (WWAV) infections, 643–645 Wildlife, rabies virus infections in, 367, 369, 375, 378–379 Wisconsin, virology services in, 667 WNV, see West Nile virus (WNV) entries WU virus infections, 421 WWAV (Whitewater Arroyo virus), 643–645 Wyoming, virology services in, 667 X Xenotropic murine retrovirus, 579 Xpect Flu A&B method, 97 Y Yaba monkey tumor virus, 529, 538 Yatapoxvirus(es), 528–531 Yatapoxvirus infections diagnosis of, 524–528 treatment of, 537–538 Yellow fever (YF) virus biology of, 394–395 vaccines for, 398 Yellow fever (YF) virus infections diagnosis of, 107, 391, 392 epidemiology of, 397 history of, 387 risk factors for, 393 Yield reduction assay, 138 Z Zanamivir for influenza virus infections, 212 susceptibility testing of, 137–138 Zanck assay, in HSV infections, 440 Zidovudine, for ATLL, 611 Zoonotic diseases, see Animals Zoster, 464–465, 469; see also Varicella-zoster virus ZymeTx methods, for antigen detection, 98 vip.persianss.ir ... 20 03; Avalos-Bock, 20 05; Busch et al., 20 05; Hoekstra, 20 05; Kusne and Smilack, 20 05; Kuehn, 20 06; Lee and Biggerstaff, 20 06; Montgomery et al., 20 06; O’Leary et al., 20 06; Hinckley et al., 20 07)... al., 20 06; Guirakhoo et al., 20 00; Huang et al., 20 00; Kochel et al., 20 00; Konishi et al., 20 00; Monath et al., 20 00; Chang et al., 20 01; Davis et al., 20 01; Huang et al., 20 03; Monath et al., 20 03;... 2D4-1 2A2C-3 EEE virus 1B5C-3 1B1C-4 1A4B-6 Flaviviruses SLE virus 6B5A -2 4A4C-4 6B6C-1 JE virus JE314H 52 6B4A-10 6A4D-1 MVE virus 4B6C -2 YF virus 5E3 2D 12 864 117 DEN virus D2-1F1-3 3H5-1 -21 D6-8A1-12