(BQ) Part 2 book Principles and practice of clinical virology has contents: Measles virus, rabies and other lyssavirus infections, human parvoviruses, human retroviruses, the human polyomaviruses, human immunodeficiency viruses, human prion diseases,... and other contents.
22 Measles Virus Sibylle Schneider-Schaulies and Volker ter Meulen Department of Virology and Immunobiology, University of Wăurzburg, Wăurzburg, Germany INTRODUCTION Acute measles is normally a mild disease contracted by children and young adults as a result of infection by the highly contagious measles virus (MV) (ter Meulen and Billeter, 1995) MV is an efficient pathogen, persisting in nature in populations large enough to support it, even though it causes an acute infection in any individual only once in a lifetime Despite this, the virus is distributed worldwide and is antigenically stable With the advent of molecular epidemiology, however, the existence of MV genotypes has been confirmed MV has no animal reservoir, and although monkeys are susceptible to infection, transmission from animals is not an important means of introducing the disease into a human community MV may persist for years in a single individual, yet these infections are rare and not associated with periodic shedding of infectious virus as seen with herpesviruses A single attack of measles is sufficient to confer lifelong immunity to clinical disease upon reinfection, even in the absence of re-exposure to the virus Consequently, in order to remain endemic in a given community, the virus must rely on the infection of the young who are still susceptible So efficient is the process that the first known report of measles (in Egyptian hieroglyphics) failed to recognize the infectious nature of the illness, and described it as a normal part of child growth and development In the pre-vaccine era in developed countries the maximum incidence of measles was seen in children aged five to nine years Infections and epidemics centred around elementary schools, and younger children acquired measles as secondary cases from their school-age siblings By the age of 20, approximately 99% of subjects tested had been exposed to MV With the introduction of the measles vaccine the age incidence and percentage of cases in Principles and Practice of Clinical Virology, Sixth Edition © 2009 John Wiley & Sons Ltd ISBN: 978-0-470-51799-4 different age groups has changed markedly In countries with an optimal vaccine utilization, measles infection has shifted to the teenage group, whereas in areas with ineffective vaccine programmes children up to four years of age reveal a high primary measles attack rate (Centers for Disease Control and Prevention, 1991, 1996) In contrast, in developing countries measles has its greatest incidence in children under two years of age Here, case fatality rates range from to 5% and can reach 30% in refugee camps and comparable settings, with malnourishment, crowding and intensity of exposure being major determinants of severity and mortality (Moss, 2007) Although a safe and efficient vaccine has been available for over four decades, measles still is a leading cause of death for young children The Measles Initiative, a partnership between the World Health Organization (WHO), the United Nations, the US Centers for Disease Control and Prevention (CDC), the American Red Cross and other organizations, was launched in 2001 and has since been developing and implementing comprehensive strategies for sustainable measles mortality reduction As a result, measles deaths worldwide fell from an estimated 873 000 (1999) to 345 000 in 2005 (Wolfson et al., 2007; www.measlesinitiative.org/index3.asp) THE VIRUS Although measles has been known for centuries, it was only with the isolation of the virus by Enders and Peebles in 1954 that experimentation became possible The development of tissue culture systems, the availability of monoclonal antibodies and molecular biological approaches then permitted insight into viral structure and replication Functional studies on MV control regions and Edited by A J Zuckerman, J E Banatvala, B D Schoub, P D Griffiths and P Mortimer 534 Principles and Practice of Clinical Virology, Sixth Edition Genomic RNA encapsidated with N protein Phosphoprotein (P) Polymerase protein (L) Matrix (MA) protein layer Glycoprotein complex: fusion (F) and hemagglutinin (H) protein (a) N P/V /R/C M F H L MV genome mRNAs + Genomic and antigenomic RNAs − (b) Gene boundary Bicistronic and genomic RNAs Proximal gene Consensus sequence Distal gene (A) auUAaaaA(3–4) CuU mRNAs AGGA/GtccAaG P/L (c) Figure 22.1 (a) Diagrammatic representation of the measles virus particle (b) MV mRNAs are sequentially transcribed from the genome with decreasing efficiency and encode the structural proteins In addition, the second gene (the P gene) encodes three nonstructural viral proteins C, R and V (c) At the gene boundaries, MV genes are separated by conserved intergenic regions where the polymerase complex stutters to polyadenylate the proximal mRNA to subsequently reinitiate transcription of the downstream gene Alternatively, these signals are neglected by the polymerase when bi- or polycistronic mRNAs are transcribed as well as during genome replication Measles Virus proteins extensively benefited from the establishment of a plasmid-driven reverse genetic system which allowed construction and rescue of infectious MVs in tissue culture that carry stable alterations in their genomes (Radecke et al., 1995) Thus, within limitations imposed by the fitness of the mutated recombinant virus, the contribution of single viral gene products within the viral life cycle in tissue culture, but also in experimental infection in animals can be addressed Meanwhile, a plethora of recombinant MVs have been generated, expressing extra reading frames such as fluorescent or enzymatically active marker genes, which allow tracing of viral replication after experimental infection, and cytokine genes Moreover, targeted interaction of recombinant MV with its natural or other, desired host cell receptors has been widely studied to gain insight into basic determinants of viral tropism, but also for potential application of systemic, targeted delivery in cytoreductive regimens for malignancies (Iankov et al., 2007) The use of recombinant MV carrying heterologous viral genes (e.g simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV) genes) as multivalent vectors for immunization has been explored, although this has been limited to animal studies so far (Tangy and Naim, 2005; Zuniga et al., 2007) MV is a member of the Mononegavirales which comprises the Rhabdoviridae, Filoviridae, Henipaviridae, Bornaviridae and Paramyxoviridae As a paramyxovirus, MV has structural and biochemical features associated with this group, but because it lacks a virion-associated neuraminidase activity it is grouped into a separate genus, Morbillivirus, of which Measles virus is the type species Other members include: Peste-des-petits-ruminants virus (PPRV), which infects sheep and goats, Rinderpest virus (RPV), which infects cattle, Canine distemper virus (CDV), which infects dogs, Phocine distemper virus (PDV), which infects seals and sea-lions, Dolphin morbillivirus (DMV) and Porpoise morbillivirus (PMV) All these viruses exhibit antigenic similarities, and all produce similar diseases in their host species Both MV and CDV can persist in the central nervous system (CNS) in their natural hosts and produce chronic neurological diseases VIRUS MORPHOLOGY Measles virus particles consist of a lipid envelope surrounding the viral ribonucleoprotein (RNP) complex, which is composed of genomic RNA associated with proteins (Figure 22.1a) The MV transmembrane fusion (F) and haemagglutinin (H) proteins project from the envelope surface of the particle, extend through the lipid bilayer into the cytosol It is the N-terminus of the H 535 protein that protrudes through the cytoplasmic and viral membranes (type II glycoprotein), while the F protein is anchored near the C-terminus (type I glycoprotein) One or both of the cytoplasmic domains are believed to interact physically and functionally with the matrix (M) protein (Tahara et al., 2007), which, in turn, links the envelope to the RNP core structure The viral genomic RNA is fully condensed with N (nucleocapsid) protein to form the RNase-resistant RNP core structure In vitro experimentation suggests that the virion is able to package more than one genome as long as the ’rule of six’ (see below) is maintained (Rager et al., 2002) As the viral genome cannot serve as mRNA, the viral polymerase complex consisting of the P (phospho-) and L (large) proteins is part of the RNP core Their location within this complex is as yet unknown, as is that of cellular actin, known to be also packaged into the virion structure The virions are highly pleomorphic, with an average size of 120–250 nm In an electron micrograph the virion is bounded by a lipid envelope which bears a fringe of spike-like projections (peplomers) 5–8 nm long (Figure 22.2a) The membrane below the spikes is 10–20 nm thick and encloses the helical viral RNP core which has a diameter of 17 nm and a regular pitch of nm Immediately below the membrane M proteins appear as a shell of electron-dense material GENOME STRUCTURE The viral genome is a nonsegmented RNA molecule of negative polarity that is about 16 kb in length The genome encodes six structural genes for which the reading frames are arranged linearly and without overlap in the following order: nucleoprotein (N, 60 kDa), phosphoprotein (P, 70 kDa), matrix protein (M, 37 kDa), fusion protein (F, disulfide-linked 41 kDa F1 and 22 kDa F2 proteins, cleavage products of a 60 kDa precursor F0 protein), haemagglutinin protein (H, 80 kDa, existing as disulfide-linked homodimer) and the large protein (L, 220 kDa) encoded on its end (Figure 22.1b) (Rima et al., 1986) The genome is flanked by noncoding leader and trailer sequences that contain specific encapsidation signals and the viral promoters used for viral transcription and/or replication (Parks et al., 2001) The genomic RNA molecule is entirely complexed with N protein with one N molecule covering six nucleotides This is thought to be the reason why only viral genomes (also including recombinant MVs carrying extra transcription units) whose number of nucleotides is a multimer of six are efficiently replicated by the viral polymerase Transcription of the viral monocistronic mRNAs is initiated within the leader sequence The coding regions of the viral genome are separated by 536 Principles and Practice of Clinical Virology, Sixth Edition intergenic regions which consist of a polyadenylation signal at the of each gene, a trinucleotide (CUU, except for CGU at the H/L gene boundary) and a reinitiation signal for the distal gene (Figure 22.1c) (Parks et al., 2001) From the P gene, three nonstructural proteins, C (20 kDa), V (46 kDa) and R (46 kDa) are expressed Whereas the C protein is encoded within a separate reading frame, V protein is translated from edited P mRNAs where a non-encoded G residue is co-transcriptionally inserted at a particular site by an intrinsic activity of the MV polymerase It thus shares the N-terminal domain with P protein, yet has a unique cysteine-rich C-terminal domain About 50% (to yield V protein) of the P mRNAs are edited At the M–F gene boundary a GC-rich region of about kb in length spans the 3’ end of the M gene and the 5’ end of the F gene Several open reading frames have been predicted for this region which could only be accessed by translation from a bicistronic transcript by ribosomal reinitiation None of the putatively encoded proteins has yet been detected in infected cells (a) MV PROTEIN FUNCTIONS The Viral RNP and Nonstructural Proteins (b) Figure 22.2 (a) Electron micrograph of the measles virion (bar = 50 nm) (b) Electron micrograph of purified MV nucleocapsids (bar = 50 nm); both are negatively stained with phosphotungstic acid (Source: Reproduced with permission from Meadeley, C.R (1973) Virus Morphology, Churchill Livingstone, Edinburgh.) The fully encapsidated MV genomic RNA serves as a unique target for the viral polymerase to initiate transcription and replication The N protein, which is phosphorylated at serine and threonine residues, is the most abundant of the MV proteins and acts to condense the viral genomic RNAs into a smaller, more stable and more readily packaged form This gives the nucleocapsid its helical form and ‘herringbone’ appearance in the electron micrograph (Figure 22.2b) When expressed in the absence of viral RNA, N proteins self-aggregate into nuclear and cytoplasmic nucleocapsid-like structures The N-terminal 398 amino acids are important for self-aggregation and RNA interaction, while the C-terminal 125 amino acids protrude from the nucleocapsid This particular domain reveals an intrinsically disordered structure (Longhi et al., 2003) and interacts with cellular proteins such as Hsp72 and IRF-3 It is by formation of high-affinity protein complexes with the phosphorylated P protein, that self-aggregation and nuclear localization of N proteins are prevented during replication of the viral genome Similar, interaction with the P protein is essential for folding of the C-terminal domain of the N protein (Johansson et al., 2003) Both the C-terminal and N-terminal domains of P protein are important for N/P complex formation, while another C-terminal motif is essential for oligomerization of the P protein Phosphorylation on serine residues is crucial for its polymerase cofactor activity in transcription and replication Stable complexes between P and L are equally Measles Virus important for these processes The L protein is a multifunctional RNP-specific RNA polymerase producing mRNAs, replicative intermediates and progeny viral genomic RNAs Capping, methylation, editing and polyadenylation are thought to be mediated by the polymerase protein in addition to initiating, elongating and terminating ribonucleotide polymerization Active sites within the protein have not yet been determined, but conserved motifs were identified which suggest a linear arrangement of the functional domains Although largely considered as typical cytosolic and nonstructural (such as V protein), C protein was found to shuttle between nucleus and cytoplasm and also to associate with viral particles (Devaux and Cattaneo, 2004; Nishie et al., 2007) Recombinant MVs defective in either V or C protein functions apparently replicated well in tissue culture cells (Radecke and Billeter, 1996; Schneider et al., 1997), yet there is evidence that these proteins regulate the efficiency of MV replication in primary cells or modulate both viral gene expression and induction of or sensitivity to the cellular interferon (IFN) response (Cruz et al., 2006; Escoffier et al., 1999; Nakatsu et al., 2006; Palosaari et al., 2003; Takeuchi et al., 2003) More recently, P protein was found to inhibit IFN signalling as well (Devaux et al., 2007) Not surprisingly, absence of V and C proteins affects MV virulence in animal models (Tober et al., 1998; Valsamakis et al., 1998) The Envelope Proteins The RNP core structure is enclosed by a lipid envelope which contains two glycosylated proteins on its external surface, the H and the F protein, which are organized as functional complexes The H protein mediates binding to cellular receptors, the F protein causes fusion of viral and cell membrane at neutral pH Both H and F protein are protease-sensitive and can be isolated by gentle detergent lysis of virions, although F protein tends to remain strongly associated with cellular actin The tendency of spikes to aggregate most likely resides in the hydrophobic tail of each molecule, which normally serves as anchor in the lipid bilayer The H protein can be isolated as a tetrameric complex from the cell membrane and efficiently agglutinates red blood cells from sheep and monkeys, but not humans Glycosylation occurs within a region of 70 amino acids, and is essential for haemadsorption, probably by stabilizing the highly complex tertiary structure of the protein Analogous to that of its Newcastle disease virus (NDV) orthologue, the ectodomain of the MV H protein is thought to be organized into a membrane proximal stalk and a membrane distal globular head region composed of a six-wing propeller (Crennell et al., 2000) Seven residues located within the globular head domain are 537 essential for oligomerization and folding of the H protein, and a cysteine residue in the stalk regions for formation of disulfide-linked dimers In addition, amino acids involved in binding of the H protein to the MV receptors were identified These, located in the ectodomain, include amongst others, residues 451, 481, 546 and 473–477 (Vongpunsawad et al., 2004) As revealed by transfection experiments, the H protein also exerts a helper function in F-mediated membrane fusion, probably by directing the fusion domain into the optimal distance to the target cell membrane and stabilizing the interaction Synthesized as a precursor protein (F0 ), F protein is cleaved in the Golgi compartment by subtilisin-like proteases to yield two disulfide-linked subunits, F1 and F2 Glycosylation of the F0 precursor is an essential prerequisite for cleavage, and all the potential N-glycosylation sites reside within the F2 subunit Mutations of any of these sites affect cell surface transport, proteolytic cleavage, stability and fusogenic activity of the F protein Indeed, the contribution of the F2 subunit to MV fusion has been directly documented (Plemper and Compans, 2003) The F1 subunit reveals an N-terminal stretch of hydrophobic residues (the fusion domain) and two amphipathic α-helical domains, one of which is adjacent to the fusion domain (HRA) and the other (containing a leucin-zipper motif) is next to the N-terminal of the transmembrane region (HRB) The fusogenic domain within the F1 subunit is masked during intracellular transport by intramolecular folding, and this most likely prevents fusion of internal membranes (Doyle et al., 2006) A central region mediates interaction with the H protein Homo- and hetero-oligomerization of the glycoproteins occurs in the endoplasmic reticulum and both interaction strength and fusogenicity of the complex are influenced by their cytoplasmic tails, both independent and dependent of their interaction with the M protein (Plemper et al., 2002) The fully processed F1/2 protein is incorporated into the cell membrane as an oligomer In the intact virion the active site of each protein is presumably carried at the tip of the spike and orientated outwards, away from the hydrophobic tail and towards any possible target cell The M protein interacts with the viral RNP and with the plasma membrane When expressed in the absence of other MV proteins, the protein promotes formation of virus-like particles confirming that, in analogy to its functional orthologues, it essentially triggers late steps in the viral life cycle such as assembly site and budding (Pohl et al., 2007) Consequently, recombinant MVs carrying deletions within the M gene bud highly inefficiently Physical interaction between M and other viral structural proteins has been difficult to demonstrate, however, M protein modulates the fusogenic activity of the F/H complex and interactions with the glycoprotein cytoplasmic 538 Principles and Practice of Clinical Virology, Sixth Edition tails allow the M protein to co-segregate to the apical surface in polarized cells A recombinant MV defective for the expression of the MV glycoproteins (expressing the glycoprotein of vesicular stomatitis virus instead) revealed the requirement of the MV glycoproteins for packaging the M protein into mature budding virions THE REPLICATION CYCLE Measles Virus Receptor Usage and Tropism One of the most important parameters determining viral tropism is the availability of specific surface receptors on susceptible cells MV naturally only replicates in primate hosts In vivo it reveals a pronounced tropism for cells of the haematopoietic lineage, but may, however, at later stages, also replicate in a variety of cell types as it does in tissue culture Thus, the receptor would be expected to be expressed by most human cells both in vivo and in vitro This is true for the first MV receptor identified, CD46 (Griffin and Bellini, 1996), which reveals a wide tissue distribution in vivo, and, notably, is expressed on monkey but not on human erythrocytes Several isoforms of CD46 (due to alternative splicing of a precursor mRNA) are expressed in a tissue-specific manner and all of them support MV uptake CD46 contains four repetitive conserved subunits within its ectodomain, with the two most membrane distal being essential for binding of the MV H protein The molecule‘s physiological ligand(s), complement components C3b/C4b, bind to membrane-proximal domains (Figure 22.3) As a member of the regulators of complement (RCA) gene family, CD46 is involved in protecting uninfected cells from complement-mediated lysis by recruiting the C3b/C4b components, thereby rendering them accessible to degradation by serum proteases It is considered of pathogenic importance that CD46 is downregulated from the surface of infected cells or following interaction with MV H protein, as these cells are significantly less protected against complement-mediated lysis in vitro (Schneider-Schaulies et al., 1995) The inability of certain MV strains, particularly those isolated and passaged exclusively on lymphocytes, to use CD46 as receptor soon indicated the existence of additional MV receptor(s), and this led to the identication of CD150 (also referred to as signalling lymphocyte activation molecule, SLAM), a CD2-like molecule of the Ig superfamily, as MV receptor (Tatsuo and Yanagi, 2002) CD150 is expressed by activated and memory T and B cells, CD46 (MCP) CD150 (SLAM) Regulates susceptibility of cells to complement (binds C3b and C4b, cofactor for inactivation) Costimulatory molecule for proliferation, IFN-γ synthesis V C2 -> Receptor for vaccine strains COOH -> Receptor for all measles strains COOH TxYxxV/I/A O-glycosylation N-glycoylation Figure 22.3 Schematic representation of CD46 (MCP, membrane cofactor protein) (left), the major protein receptor for attenuated MV strains MV-binding sites are located within the short consensus repeat (SCR) domains and 2, whereas complement components C3b/C4b bind to SCR and 4, respectively Proximal to the transmembrane domain, oligosaccharide-rich serine/threonine/proline (STP) domains are located CD150, a member of the Ig superfamily, (right) is the receptor of all MV strains tested as yet MV binding occurs at the membrane distal domain (the V domain) Glycosylation sites in the extracellular domains are indicated as are residues in the cytoplasmic domain identified as important for signalling Measles Virus and immature thymocytes, but not by freshly isolated monocytes and immature dendritic cells, where expression of this molecule is inducible For monocytes, this can occur by interaction of the H protein of wild-type MV strains with Toll-like receptor (TLR2), which itself does not serve as an entry receptor (Bieback et al., 2002) As for CD46, the most membrane-distal portion of CD150, the V domain, is important for MV binding, and CD150 is also downregulated in response to infection or H protein interaction CD150 supports entry of all MV strains known, yet its expression is confined to haematopoietic cells, and thus, alternative MV entry receptors should exist, promoting uptake of wild-type MV into cell types such as endothelial, epithelial (during acute measles) and brain cells (as prerequisite for CNS persistence) (Yanagi et al., 2006) The contribution of the MV receptors to MV tissue tropism and pathogenicity is not yet understood Rodents genetically modified to express CD46 or CD150 are not susceptible to MV infection unless the virus is intrathecally applied Most likely, as yet unknown intracellular factors efficiently restrict MV replication in rodent cells Infection of brain cells in vivo, on the other hand, can occur independently of CD46 expression as documented in mice or rats after intracerebral infection with an attenuated, rodent brain adapted MV strain In cotton rats which are susceptible to intranasal infection with both attenuated and wild-type MV strains (as revealed by virus isolation from peripheral blood mononuclear cells (PBMCs), development of interstitial pneumonia and immunosuppression) tissue distribution of potential CD150 and CD46 ortho- 539 logues has not been evaluated due to the lack of appropriate reagents It has been shown, however, in these animals that infection with the wild-type MV strain or recombinant viruses expressing the wild-type MV H glycoprotein leads to preferential infection of secondary lymphoid tissues and pronounced immunosuppression These findings lend strong support to the essential role of the interaction of the MV H protein with its receptors in MV pathogenesis in vivo Intracellular Replication The time taken for MV replication in a host cell is variable and becomes shorter as the virus adapts to growth in vitro For instance, the Edmonston strain replicates well in Vero cells, an African green monkey kidney cell line, where growth is complete within 6–8 hours and accompanied by effective inhibition of host cell macromolecular synthesis Other strains, particularly freshly derived isolates, grow more slowly and replication times of 7–15 days are not uncommon Such viruses often have very little inhibitory effect on the biosynthesis of the host cell The origin and activation stage of the host cells also influence the efficiency of MV replication as does their ability to produce type I IFN or, in turn, the ability of the virus strain to prevent IFN production and/or signalling Following delivery of the viral RNP complex into the cytoplasm, viral transcription is initiated after specific attachment of the polymerase complex to the promoter located within the end of the genome and progresses to the end by transcribing mono- and bicistronic mRNAs (Figure 22.4) At each gene boundary, the polymerase complex resumes transcription of the distal Rough ER g Golgi H, F L, N, P Nucleus M Figure 22.4 Schematic representation of the events occurring in measles virus replication 540 Principles and Practice of Clinical Virology, Sixth Edition gene or leaves the template As a consequence, a polar gradient is established for the frequency of viral mRNAs with the N-specific mRNA being the most abundant and the L-specific mRNA the least represented (Figure 22.1b) At the end of each gene, poly(A) tracts are added to the mRNA transcripts, most probably by a polymerase stuttering mechanism at the termination signals (Figure 22.1c) Bi- and polycistronic polyadenylated transcripts spanning two or more adjacent genes are also produced In the replication mode, the polymerase complex reads through the intergenic boundaries to yield a positive-sense replicative intermediate which is about 100-fold less abundant than that of negative polarity Transcripts of positive polarity containing the encapsidation signal at their end joined to the N gene sequence are indicative of antigenome replication Replication of, but not primary transcription from viral genomic RNA is dependent on protein synthesis, and the switch to the replication mode is possibly determined by the accumulation levels of N protein that has to encapsidate the nascent genome and may act as an anti-terminating protein Not surprisingly, expression and/or function of the L protein are currently targeted by RNA interference approaches or non-nucleoside inhibitors in vitro in order to exploit inhibition of the polymerase for therapy (White et al., 2007) The viral mRNAs direct the synthesis of viral proteins which are translocated and, in case of the glycoproteins, modified through the Golgi apparatus (acquisition of N-linked glycosylation and proteolytic cleavage of the F0 protein) and finally inserted into the plasma membrane The F protein associates preferentially with membrane microdomains (also referred to as lipid rafts) and most likely drags the H protein into these structures from where the virus subsequently buds Nascent RNA genomes condense with N protein to form the nucleocapsid, and P and L proteins bind to these structures in the perinuclear area Late in infection, nucleocapsids may also enter the cellular nucleus M protein combines with both cytoplasmic nucleocapsids and plasma membrane resident virus glycoproteins, and possibly interacts with cytoskeletal components during intracellular transport of viral RNPs Progeny nucleocapsid structures line up beneath these modified areas of the membrane and are pinched off in the budding process The ability of M protein to aggregate in a crystalline array most likely enables distortion of the membrane into an outward-facing bulge, and ultimately budding of the nucleocapsid inside a small vesicular structure –the new virion (Figure 22.4) During the replication process the large amount of glycoprotein inserted into the cell membrane causes it to develop the capacity to attach to adjacent cells, while the F protein promotes fusion with adjacent cells Multinucleate giant cells are thus formed which are pathognomonic for measles infection Host cells are rapidly killed by fusion, and if this is prevented both survival and virus production are increased BIOLOGICAL PROPERTIES OF THE MEASLES VIRUS Stability The structure of the virion explains much of the early data concerning the stability and infectivity of the virus, which depends on the integrity of the envelope Hence the virus is sensitive to any procedure which disrupts this structure, such as detergents or other lipid solvents, including acetone or ether Particles are acid labile and inactivated below pH 4.5, although they remain infective in the range pH 5–9 The virus is also thermolabile It may remain infective for two weeks at ◦ C, but it is completely inactivated after 30 at 56 ◦ C At 37 ◦ C it has a half-life of hours Thermolability is probably due to an effect on the internal structure of the particle since haemagglutinin is relatively temperature-resistant Virus can be stored for prolonged periods at −70 ◦ C and also freeze-dries well These properties have important consequences for the transport and storage of vaccine Haemagglutinin MV displays haemagglutination activity for erythrocytes from rhesus, patas and African green monkeys and baboons, but not from humans The H protein mediates attachment to susceptible cells, and consequently, the ability to cross-link erythrocytes which not support virus replication represents an unnatural process in virus multiplication Thus the inability to agglutinate erythrocytes from the primary host, which is based on the lack of the major MV receptor component CD46 on these cells, is not surprising Morbilliviruses have no neuraminidase activity and not attach to receptors containing sialic acid Consequently, once attached to a red blood cell, MV does not re-elute rapidly H protein inserted into any membranous structure is active in the haemagglutination test Virus particles separated by isopycnic centrifugation have a buoyant density of 1.23 g cm−3 and haemagglutination activity is detected in this area of the gradient A large amount of haemagglutinating material is also found in the upper regions of the gradient (termed light haemagglutinin) which probably represents H protein inserted into empty membranous fragments of infected cells, or defective virus particles Haemagglutinating activity in this fraction can exceed Measles Virus that associated with the intact particles Notably, MV wild-type strains isolated on B lymphoid cells and not adapted to grow on Vero cells have very low haemagglutination activity This may be caused by the presence of an additional N-linked glycosylation site within their H proteins, but is best explained by their inability to interact with CD46 on monkey erythrocytes H protein is the major immunogen of the virus, and antibodies directed against this protein have both haemagglutination inhibition (HAI) and virus-neutralizing activities (neutralizing test, NT) However, these antibodies cannot prevent the progressive viral cell-to-cell spread mediated by the F protein The function of H protein as the major viral attachment protein and downregulation of host cell receptor(s) has already been outlined above Moreover, receptor ligation by H protein can trigger signalling pathways in host cells, and this may relate to certain aspects of MV-induced immunosuppression (see below) Haemolysis The ability to lyse red blood cells once the virus has bound is mediated by the viral F protein This ability is artificial in the same way that haemagglutination is artificial, since the F protein is not normally called upon to lyse a target cell before productive infection is accomplished Nevertheless, haemolysis (HL) provides a convenient measure of F protein activity which is more sensitive to pH and temperature than haemagglutination The optimum temperature for HL is 37 ◦ C and optimum pH is 7.4 The ability of paramyxoviruses to fuse at neutral pH accounts for their characteristic cytopathic effect (CPE), the formation of giant cells Proteolytic activation of the F protein is vital for its activity; although uncleaved molecules can be inserted into mature virus particles, these not fuse with target cells and are therefore not infectious Insertion of the N-terminal hydrophobic fusion domain of the F1 subunit is thought to have a destabilizing effect on the local structure of the target cell and synthetic peptides with similarity to this region but also those corresponding to the heptad repeat regions (which inhibit back-folding of the F1 subunit into its fusion active conformation after MV receptor interaction) efficiently impair cell fusion Antibodies directed against the F protein are required for effective containment of virus infection, which can be maintained locally by cell-to-cell fusion Given the importance of this protein for cell entry, it is not surprising that structurally conserved microdomains within the F protein are exploited as potential target sites for rationally designed antiviral compounds (Plemper et al., 2004, 2005; Sun et al., 2006) 541 EPIDEMIOLOGY AND RELATEDNESS OF DIFFERENT VIRUS ISOLATES The efficient spread of the virus is mediated by aerosol droplets and respiratory secretions, which can remain infectious for several hours The disease incidence in the northern hemisphere tends to rise in winter and spring when lowered relative humidity would favour this form of transmission In equatorial regions epidemics of measles are less marked but can occur in the hot dry season Acquisition of the infection is via the upper respiratory tract, the nose and, possibly, the conjunctivae Virus is also shed in the urine but this is unlikely to be an important means of transmission The spread of measles is a convenient example to illustrate the principles of epidemiology; based on calculations, any community of less than 500 000 is unlikely to have a high enough birth rate to supply the number of susceptible children required for the continuous maintenance of the virus in a population In fact, complete elimination of measles from isolated groups has been documented; these remain free of the disease until MV is reintroduced from outside, and susceptible individuals are once more at risk Measles often leads to a more serious disease in such communities experiencing the illness for the first time, because all age groups are susceptible to the infection In general, measles mortality is highest in children under two years of age and in adults Death from uncomplicated measles is rare in the developed world, yet introduction of the virus to the Fiji Islands in 1875 resulted in an epidemic with a fatality rate of 20–25% and into Greenland in 1951 produced an epidemic which infected 100% of susceptibles and resulted in a death rate of 18 per 1000 MV isolates have been obtained from many different locations and from patients with different clinical conditions In serological terms, the virus is monotypic and thus infection by any MV confers immunity to them all With monoclonal antibodies, antigenic differences between vaccine and wild-type viruses can be observed, though these could not be linked to pathogenicity, replication or transmission The monotypic nature of MV has masked the existence of a set of genotypes which accumulate mutations continuously Extensive studies on the molecular epidemiology of MV failed to reveal the existence of MV strains with different pathogenic potential (lymphotropism and neurovirulence, the latter more likely to cause subacute sclerosing panencephalitis (SSPE)) or potential antigenic drift in wild-type MV strains that may impair the protective effect of the current vaccine They have been highly instrumental in populations where mass vaccination campaigns have been undertaken, because they allow us to define whether any single measles case is due to an imported virus or represents a still unadequate 542 Principles and Practice of Clinical Virology, Sixth Edition vaccine coverage or vaccine failure Thus, in 1995, 60% of the 309 cases of measles reported in the United States were either directly imported or were found to be directly linked to an imported case by routine investigation or molecular epidemiology methods (Rota et al., 1992) Sequence analysis of vaccine and wild-type MV strains as well as SSPE isolates has allowed classification of these various MVs into lineage groups, referred to as ‘clades‘ (numbered A–H), and within those, different genotypes can be distinguished Genotyping of a given measles strain is based on the C-terminal 151-amino-acid sequence of the N protein, where up to 10.6% divergence in the amino acid sequence between unrelated strains can occur For most of the recent isolates, the sequence of the H gene is also available While some MV clades are more or less extinct (i.e have not been isolated for at least 15 years), others are still co-circulating (see www.cdc.gov/ncidod/dvrd/revb/measles/index.htm) The activity within a clade is directly mirrored by the heterogeneity of genetically related recent isolates which are drifting on a genetic level It is indicative of MV re-importation into regions where transmission of indigenous MV is interrupted that MVs of different, genetically unrelated genotypes are isolated during an outbreak Genetic characterization of MV is a powerful adjunct to the standard epidemiological techniques applied to study measles transmission as it helps to confirm the sources of virus or suggest a source for unknown source cases, or to establish links, or lack thereof, between cases and outbreaks Molecular surveillance is most beneficial in tracing local genotypic changes over time, and this, analysed in conjunction with standard epidemiological data, has helped to document the interruption of transmission of endemic measles and to measure the effectiveness of measles control programmes MV vaccine strains (which all fall within clade A) differ widely from wild-type isolates, and SSPE-derived sequences were closely related to those of wild-type viruses It was even possible to identify wild-type MVs that had circulated in a given population as likely infectious agents found later in SSPE brain material In the late 1980s and early 1990s, re-importation of wild-type MV of a known genotype into the United States caused about 50 000 cases In a recent study, seven cases of SSPE were noted which could clearly be assigned to the wild-type MV having caused the acute infection 10 years ago (Bellini et al., 2005) These findings resulted in three important conclusions: first, SSPE develops more frequently than thought (Bellini et al., 2005; Takasu et al., 2003), second, SSPE develops after infection with a wild-type MV and not following vaccination, and third, circulating wild-type viruses and not particular neurotropic strains access the CNS Thus, the development of complications is not determined by the virus, but rather by the susceptibility, age and immune status of the host at the time of infection The biological importance of the fact that all vaccine strains have a genotype substantially different from the currently co-circulating wild-type viruses is unclear There is, however, no evidence to suggest that the currently used vaccines are not able to control MV infection with viruses of differing genotypes CLINICAL MANIFESTATIONS Acute Measles Measles was an inevitable disease of childhood prior to the vaccine era, and thus clinical features are well documented The course of acute measles is illustrated diagrammatically in Figure 22.5 The virus first gains entry into the body through the upper respiratory tract or conjunctiva Replication is assumed to occur at the site of entry It is unknown as yet whether epithelial cells in the respiratory epithelium support MV replication, or if the first target cells are professional antigen-presenting cells (APCs) (such as monocytes or tissue-resident macrophages or dendritic cells) which acquire virus by CD150-dependent infection Whether the interaction with DC-SIGN, a lectin receptor, shown in vitro supports entry of MV into dendritic cells (DCs) or internalization in vivo is unknown APCs most likely mediate transport of MV to secondary lymphatics, where MV replicates and causes tissue destruction The virus then spreads to the rest of the reticuloendothelial system and respiratory tract through the blood (primary viraemia) Giant cells containing inclusion bodies (Warthin–Finkeldy cells) are formed in lymphoid tissues and also on the epithelial surfaces of the trachea and bronchi About five days after the initial infection the virus overflows from the compartments in which it has previously been replicating, to infect the skin and viscera, kidney and bladder (secondary viraemia) Giant cells are formed in infected tissues, which are also characterized by lymphoid hyperplasia and inflammatory mononuclear cell infiltrates After 10–11 days incubation the patient enters the prodromal phase, which lasts from two to four days The initial symptoms consist of fever, malaise, sneezing, rhinitis, congestion, conjunctivitis and cough, which increase over the next days and are quite troublesome A transitory rash of urticarial or macular appearance can sometimes develop within the prodromal phase, but this disappears prior to the onset of the typical exanthem At this time giant cells are present in the sputum, nasopharygeal secretions and urinary sediment cells Virus is present in blood and secretions, and the patient is highly infectious During this period Koplik’s spots, the 1000 monkeypox (contd.) rodent reservoir 72 smallpox relationship 630 treatment 635 monkeypox virus 625, 630 host, distribution 626 phylogeny 626 transmission 630 monkeys filovirus infections 755–756, 756–761, 763, 767–768 see also primates monocytes EBV infection 204 rhinovirus infection 495–496 Mononegavirales 373, 409, 441, 535, 766 Monongahela virus 704 mononuclear cells, atypical, EBV infection 208, 208, 210 Monospot test 210–211 Mopeia virus 734, 736, 739 antigenic relationships 741 Morbillivirus 410, 410, 535 viruses included 535 mortality, infectious diseases, USA 69, 70 mosquito-borne viruses bunyaviruses 701 control strategies 677, 678, 684, 686–687 flaviviruses 672, 673 dengue 680–681 yellow fever 674, 675 Rift Valley fever virus 712–713 see also specific mosquito genera motavizumab, RSV infection prevention 454 mouse L cells, arenavirus culture 739 MPL (3-O -desacyl-4’-monophosphoryl lipid A) 84–85 Mucambo virus 659, 660 mucociliary clearance (nasal), rhinovirus infections 493 mucosal disease virus group 670 mucosal oedema, rhinovirus infection 493, 495 mucus secretion, rhinovirus infection pathogenesis 493, 495 Muju virus 704, 722 Muleshoe virus 704 Multicentre AIDS Cohort Study (MACS) 17 multicentric Castleman’s disease (MCD) 245 clinical features 253–254 KSHV replication 257 plasma-cell and hyaline vascular variants 253 multidrug resistance gene (MDR1) 889–890 multinucleated giant cells HTLV-1 infection 876 measles virus infection 540, 543, 544, 549 VZV infections 137, 138, 140, 141, 144, 148, 149 multiple analyser systems 22 multiple sclerosis (MS) coronavirus role 522 HBV vaccine and 90 HHV-6 association 231, 234 pathogenesis 522 mumps 593–600 antibodies 594, 595 Subject Index assays 597 IgM 597 arthralgia/joint involvement 597 children 598 clinical features 595–597 community outbreaks 46 complications 596–597 endocardial fibroelastosis 597 epidemiology 598–599 hearing defect 597 history 593 hospital outbreaks 46 immunity 598 incubation period 52, 595 interferon role 595 laboratory diagnosis 597–598 antibody assays 597 virus detection 597–598 meningitis and encephalitis 595, 596–597 military personnel 593, 597 myocarditis 597 nosocomial infection 45–46 oophoritis 597, 598 orchitis 597, 598 pancreatitis 597 parotitis 595–596, 596 pathogenesis 595, 595 pathology 595 pregnancy 597 prevalence reduction by vaccination 83 reinfections 598 required vaccination coverage 82 seasonal variations 598 secondary viraemia 595 transmission route 46 vaccination 598–599 infection incidence reduction 46 meningitis risk 598–599 problems eliminated by 599 status affecting clinical features 596 virus strains 598–599 mumps virus 593–594 antigenic structure 594 classification 593 excretion/shedding 595, 596 F protein (F0, F1, F2) 594 genetic variation between strains 594 genome (negative-sense RNA) 593 genomic organization 594 growth in cell culture 595, 597 HN glycoproteins 593–594 isolation/detection 597–598 Jeryl Lynn strain 598 Leningrad–Zagreb strain 598 M protein 594 NP protein 593, 594 Paramyxovirus member cross-reaction 594 physical characteristics 50 polymerase complex 593 proteins 593, 594 receptor 594 replicative cycle 594 Rubini strain 599 serotype 598 SH protein 594 structure and physical properties 593, 594 transmission 52, 595 Urabe strain 598 vaccine strains 598–599 V antigen 594 murine hepatitis coronavirus (MHV) 512, 515, 517, 522 receptors 517, 518 murine leukaemia virus (MuLV) 872 murine noroviruses 359 murine PIV1 (MPIV1) 410 Murray Valley encephalitis 690–691 Murray Valley encephalitis virus 673, 690–691 Murutucu virus 702, 710 muscle fasciculation, rabies 790 mutation, of viruses 70–71 myalgic encephalomyelitis see chronic fatigue syndrome Mycobacterium avium-intracellulare (MAI) complex 912 Mycobacterium tuberculosis, in HIV infection 912 mycosis fungoides, HTLV-1 and 886 myelin breakdown, acute measles post-infectious encephalitis (AMPE) 548 inflammatory mediator cross-reaction 522 myelin basic protein (MBP) 548 myelitis, herpes zoster complication 147 myelopathy HTLV-1 associated see HTLV-associated myelopathy/tropical spastic paraparesis (HAM-TSP) HTLV-2 886 myelosuppression, CMV causing 175 myocarditis adenovirus infections 477 coxsackievirus group B (CVB) 609, 610–611 enterovirus infections 610–611, 612 mumps 597 neonatal enteroviral 611 myoclonic jerks, SSPE 544, 545 myoedema, rabies 790 myoglobinuria, influenza 390 myopathy chronic inflammatory, enteroviruses causing 612 idiopathic inflammatory, TTV infection and 330 myositis, influenza 390 myristic acid, enteroviruses 603 N Nairobi sheep disease virus 703, 721 Nairovirus 699, 717–721 biochemical properties 700 members and vectors 703 Nanoviridae 325 nasopharyngeal carcinoma (NPC), EBV and 199, 206, 213–215 clinical features 214 diagnosis 214, 215 seroepidemiology and pathogenesis 213–214 treatment and prevention 214–215 Subject Index WHO classification 214 national immunization days (NIDs), polio 618 natural history of viral infections 17 natural killer (NK) cells arenavirus infections 742 CMV protein interference 171–172, 172 evasion, KSHV infected cells 261 HBV clearance 292 Ndumu virus (NDUV) 644, 646 necrotizing enterocolitis, coronaviruses 522 needlestick injuries 32 HBV infection after 33, 34 HIV infection after 33, 33 negative predictive value 16 Negishi virus 673 Negri bodies 778, 779, 784, 796 nelfinavir, HIV infection 926, 927 neonatal infections CMV infection see cytomegalovirus (CMV) infection, perinatal CMV screening 180 coxsackievirus group B (CVB) 612 echoviruses 612 enterovirus infections 612 hepatitis B 293 HSV 124–127 RSV 448 rubella 570 varicella (chickenpox) 145–146 nephropathia epidemica 722 Nepuyo virus 702, 710 nerve cells, latent HSV infections 99–100 neural cell adhesion molecule (NCAM), rabies virus 783–784 neuralgia, post-herpetic, herpes zoster 133, 139, 147 neuraminidase HPIV see human parainfluenza virus(es) (HPIVs) influenza virus see influenza virus neuraminidase inhibitors (drugs) influenza 396, 398–399 structure 397 virus resistance 399 neurological complications/disease EBV infection 209 HHV-6/HHV-7 infections 232, 234, 240–241 HSV-2 infection 123 neuromuscular junctions, rabies virus infection 783 neuromyasthenia see chronic fatigue syndrome neuronal dysfunction, rabies 784 neuronal specific enolase (NSE), sporadic CJD 950 neurotrophin receptor (p75 ), rabies virus receptor 784 neutralization tests dengue 680, 683 enteroviruses 616 neutrophilia, HPIV infection 418 neutrophils 83 nevirapine HIV infection 925–926 post-exposure prophylaxis in HCWs 35 Newcastle disease virus (NDV) 410, 413 new variant Creutzfeldt–Jakob disease (nvCJD) 72, 954 see also variant Creutzfeldt–Jakob disease (vCJD) New York virus 704 NFAT1 (nuclear factor of activated T cells) HTLV-1 886, 887 JC virus binding 828 NF-κB activation, KSHV infection 259 HTLV-1 infection pathogenesis 886, 887 JC virus binding 828 rhinovirus infections 494 Ngari virus 702, 706–707 nicotinic acetylcholine receptors, rabies virus 783 Nidovirales 511 Nipah virus 75–76, 410, 424 non-Hodgkin’s lymphomas (NHL) in AIDS, EBV and 217 EBV association 206 HHV-6 association 231 in HIV infection 915–916 JC virus association 846 non-nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs) 921, 924–925 adverse effects 925 mechanism of action 925 metabolism/interactions 925–926 resistance 925, 925, 929 K103N and Y181C 925 second-generation 925 normal human immunoglobulin (NHIG) adenovirus infections 482 hepatitis A prevention 279 parvovirus B19V infection 865 noroviruses (NoVs) 355, 358–363 antibodies 361–362, 362 classification 359 diagnosis 55 diversity, genogroups and evolution 362 epidemiology 356, 361–362 by age 357 gastroenteritis due to clinical features/course 358, 361 pathogenesis 360 prevention 363 genome (positive sense ssRNA) 359, 360 GII-2 (Snow Mountain) strain 361 host genetic resistance 362 immune response 361 incubation period 54 laboratory diagnosis 360–361 nosocomial infections 54–55 management 55 outbreaks in hospitals 54 persistence in environment 49, 55 physical characteristics 50 proteins, structure/function 361 receptors 362 replication and cell culture 359–360 structure 356, 359 transfection of RNA 359 1001 transmission routes 55, 362 Norwalk virus (NV) 358 genome 359, 360 nosocomial infections/transmission 43–68 adenovirus 61 blood-borne infections see blood-borne viruses (BBVs) blood-contaminated instruments 32 CCHF virus 718 CJD 953–954 CMV 47–48 coronavirus (CoV) 521 Ebola haemorrhagic fever 760, 763 factors increasing 43 hepatitis C 32 HHV-6 230 HIV infection, prevention 931–932 HPIV 424 HSV 53–54 influenza 58–60 Lassa fever 748, 749, 750 Marburg haemorrhagic fever 756 measles 44–45 mumps 45–46 noroviruses 54–55 organ/tissue transplantation 32 parainfluenza virus 60–61 parvovirus B19 56–58 prevention 43–44 renal haemodialysis 32 respiratory viruses 58–63 risk minimisation strategies 30 rotavirus 56, 345 RSV 62–63, 443–444, 455, 455 rubella 46–47 SARS-CoV 61–62 VZV see varicella zoster virus (VZV) ward closures 43, 54, 55, 57 NoV see noroviruses (NoVs) 5’ nuclease oligoprobes, PCR 10, 11 nucleic acid detection blood/blood products 31 HSV 106–107 influenza virus 394 nucleic acid sequence-based amplification 13–14 nucleic acid sequencing, automated 20 nucleoside analogues hepatitis B 300–301, 306 HSV infections 108 JC virus infection 847 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) 921, 922–924 adverse events 922–923 HAM treatment 890 mechanism of action 922–923 resistance 921, 923–924, 924 M184V mutation see lamivudine Q151M mutation 924 nutlin 3a 263 Nyando virus 702, 708 O obesity, adenovirus infections associated 477 Ockelbo disease 648, 649 1002 Octomer binding protein (OCT-1) 98 ocular defects, congenital rubella syndrome (CRS) 572, 573–574, 574, 575 ocular infections see eye infections oligodendrocytes, in PML 840 Oliveros virus 734, 751 Omsk haemorrhagic fever 694 Omsk haemorrhagic fever virus (OHFV) 669, 673, 694 oncogenesis see cancer, oncogenesis mechanisms Oncovirinae 870 o’nyong-nyong virus 652–653 oophoritis, mumps 597, 598 ophthalmic herpes zoster 146, 147, 153 optical immunoassays (OIAs), RSV infection 451 oral hairy leukoplakia (OHL) EBV association 199, 218, 912 HIV infection 912 oral infections/lesions HIV infection 912 HSV see herpes simplex virus (HSV) infection oral rehydration solution (ORS) 344, 344, 356 Oran virus 704 orchitis mumps 597, 598 smallpox 629 orf 635–636 host, distribution 626 Oriboca virus 702, 710 ‘original antigenic sin’ 138, 382 Oropouche virus 702, 709–710 Orthobunyavirus 699, 706–711 members and transmission 702 Orthomyxoviridae 373 Orthomyxovirus, physical characteristics 50 Orthopoxvirus 625, 626 orthopoxviruses 625–635 antibodies and serology 633 antigens 626 A-type inclusions 627 B-type inclusions 632 cell culture 632 genome (dsDNA) 626–627 hosts, distribution and disease 626 immunofluorescence (IF) 633 lateral bodies 625–626, 627 mRNA and transcription 627 PCR 633, 634 phylogenetic relationships 626 replication 626–627, 630, 635 structure/morphology 625–626, 627 orthopoxvirus infections 627–632 clinical features 627–632 diagnosis 632–634 immunodiagnosis 633 laboratory diagnosis and specimens 632 management 634–635 nucleic acid diagnosis 633–634 passive immunization 635 phenotypic diagnosis 632–633 treatment (antivirals) 635 vaccination 634–635 Subject Index see also cowpox; monkeypox; smallpox oseltamivir HPIV infection 429–430 influenza 60, 398 H5N1 399 structure 397 Ossa virus 702, 710 osteitis deformans, measles virus associated 545 osteomyelitis, in smallpox 629 otitis media acute, rhinovirus infection complication 497–498 with effusion (OME) coronavirus infection 520 rhinovirus infection 497 influenza 390 RSV infection 448 otosclerosis, measles virus associated 545 outcome of viral infections, host factors affecting ‘owl’s eye’ intranuclear inclusions 161, 176–177 oxygen, supplemental RSV infection 452 SARS prevention recommendations 62 P p53 adenovirus as vector 482 BK virus oncogenicity 843 inactivation, HTLV-1 infection 886 inhibition, KSHV infection 257 JC virus TAg interference 842 KSHV infection treatment 263 Paget’s disease, measles virus associated 545 pain, zoster-associated see zoster-associated pain (ZAP) palivizumab, RSV infection 63 prevention 454–455 pancreatitis acute, coxsackievirus group B 614 mumps 597 P antigens, receptor for B19V 857–858 panuveitis, HSV 118 Papillomavirus 807 papillomaviruses 807–822 cell/tissue culture 811–812 chemical properties 807–810 classification 807, 808 clinical features of infection 807 diagnosis 817–818 early (E) proteins 808–809 genome (dsDNA) 807–810, 809, 810–811 late (L) proteins 808–809, 811 mRNA transcription 808–809 natural history of infections 812–813 persistence in environment 49 physical characteristics 50, 807–810 proteins 808, 810, 810–911 replication 811–812 serology 811 structure 807, 808 supergroups (A-E) 807, 808 transmission 813 vaccination 819–820 virus-like particles (VLPs) 811 see also human papillomavirus (HPV) Papovaviridae 807, 823 papovaviruses persistence in environment 49 see also human polyomaviruses; papillomaviruses pappataci fever 711 parainfluenza viruses 409–439 animal infections 417 animal viruses 409–410 antigenicity and immunity 418–420 cell culture and tissue tropism 416 chemokines and cytokines 417 detection 425–427 infections incubation period 52, 416 inflammation due to 417, 418 mortality 60 nosocomial 60–61 pathogenesis 417–418 prevention 428–429 seasonal outbreaks 60 see also human parainfluenza virus(es) (HPIVs) life cycle 411, 412 physical characteristics 50 receptors, attachment and host range 411–414 replication 414–416 shedding 417 structure and properties 410–411, 412 taxonomy 409–410, 410 transmission 52, 60–61, 416–417 paralysis, acute flaccid 609 West Nile fever 690 Paramyxoviridae 409, 410, 441, 593 emerging viruses 76 Paramyxovirinae 409, 410 Paramyxovirus, physical characteristics 50 paramyxoviruses new/emerging 75–76 replication 415 Paran´a virus 734 parapoxvirus, host, distribution 626 parapoxvirus infections 635–636 clinical features 635–636 diagnosis, and control 636 pathogenesis 635 parasympathetic nervous system, rhinovirus infection pathogenesis 495 paravaccinia 635 parechoviruses see human parechoviruses (HPeVs) Parkinson’s disease 390 parotid gland, mumps 595–596 parotitis, mumps 595–596, 596 particle agglutination assays 4–5 Parv4 virus 853, 854 Parvoviridae 853 Parvovirinae 853 groups/classification 853, 854 Parvovirus, physical characteristics 50 parvovirus B19 see human parvovirus B19 (B19V) Subject Index parvoviruses 853–867 acute diarrhoeal disease 365 animal 853, 862, 865 autonomous 853, 854 emerging/new 74 genomic organization 854–855, 855 human see human parvovirus B19 (B19V) structure 356 passive T-cell immunotherapy, CMV 185 Pasteur, Louis 81, 777 pathogen-associated molecular patterns (PAMPs) 83, 84 pattern recognition receptors (PRRs) 83, 84, 547 Pc (proportion of persons immune) 82 pegylated interferon see interferon penciclovir herpes zoster 152 HSV infection 111 structure 109 penile cancer, HPV and 815 ‘pentaplex’ assay 12 pentosan polyphosphate, CJD 961 ‘peptide assay’, HIV 908 peramivir influenza 398 structure 397 Pergamino virus 704 pericarditis, enteroviral 616 perinatal infections, tests for 21 persistence of viruses in environment 49 pertussis, prevalence reduction by vaccination 83 pertussis syndrome, adenovirus serotypes 472, 473 Peste-des-ruminants virus (PPRV) 535 Pestivirus 669, 670 pharyngeal obstruction, EBV infection 209 pharyngitis EBV infection 208 Lassa fever 748 pharyngoconjunctival fever (PCF), acute 471, 472 adenovirus serotypes 472, 474 phenotypic assays antiretroviral drug resistance 918–919, 919, 920 antiviral resistance detection 19, 19 phlebotomus fever 711 Phlebovirus 699, 711–717 members and vectors 703 phobia, rabies 788, 790 phobic spasms, rabies 788, 789 Phocine distemper virus ( PDV) 535 phylodynamics, HIV 900 Pichinde virus 734, 737 antigenic relationships 741 genome 740 picobirnaviruses 365–366 gastrointestinal disease 365–366 Picornaviridae 277, 364, 489, 601 genera 601 Picornavirus, physical characteristics 50 picornaviruses genome 277, 277 rhinoviruses see rhinoviruses structure 356 pigs (swine) hepatitis E transmission 282 influenza virus 384 Japanese encephalitis transmission 685 Nipah virus 75–76 TTV infections 328–329, 329 Pirital virus 734, 751 plaque reduction assay 19 plaque reduction neutralization test (PRNT) arenaviruses 741 dengue virus 680, 683 plasmablasts, KSHV-infected 254 plasma leakage dengue haemorrhagic fever 682 hantavirus infections 725 platelet counts, congenital rubella syndrome 573 pleconaril poliomyelitis therapy 620 rhinovirus infections 501 PMEO-DAPym, hepatitis B treatment 305 Pneumocystic carinii pneumonia (PCP) 897, 912 pneumomediastinum, rabies 789 pneumonia adenoviruses 471, 474 atypical, serological tests 21, 22 giant cell (Hecht), in measles 544 HPIV infection 421, 423 HSV nosocomial 54 influenza 389–390 measles 473, 543, 544, 552 rhinovirus infection 498 RSV 446–447 SARS 521–522, 526 secondary bacterial in influenza 389–390, 396 in RSV infection 448 varicella 144, 144 pneumonitis CMV 174, 175, 912 HPIV infection 417 varicella (chickenpox) 152, 154 pneumothorax, adenoviruses 471 Pneumovirinae 410, 410, 441 Pneumovirus 410, 410, 441 podophyllin, HPV treatment 818 Pogosta disease 648, 649 point mutation assays (PMAs) 20 point-of-care testing (PoCT) HIV infection 907–908 influenza virus 394 polio-like illnesses 609, 613 poliomyelitis 601, 620 abortive 609 clinical features 609–610 CNS infection 609 diagnosis 615, 616–617 global eradication programme 618 in India 618 mortality 609 Nigerian outbreaks 618, 619 outbreaks 617, 619 paralytic 609–610 pathogenesis 609 1003 prevalence reduction by vaccination 83 prevention 617–620 re-emergence after eradication 620 re-introduction after vaccine use 618 supplementary immunization activities (SIAs) 618 treatment 620 vaccine-associated paralytic (VAPP) 617, 619 vaccines/vaccination 617–620 efficacy concerns 618–619 eradication programme problems 618–619 global eradication programme and 618 inactivated (IPV) 617, 619 IPV replacement of OPV 619 manufacture 619–620 oral 617, 618, 620 required coverage 82 resistance to use 618 Sabin 617 Salk 617 schedule 618 stopping of vaccination 619 type I and vaccines 619 poliovirus (PV) antigenic structure 603–604 capsid structure 603, 604 cell culture 608, 615, 617 characteristics 608 circulating vaccine-derived (cVDPV) 619 classification 607, 607 containment after eradication 619–620 genome organization 605, 606 genotypes, eradication and 618 host range 609 isolation/detection 615 as laboratory virus 619 non-polio enteroviruses differentiation 616–617 PCR 616–617 persistence in environment 49 persistence in tissues (CNS) 610 proteins and protein structure 602, 603, 604 PV1 603 PV2 603, 604, 618 PV3 604, 617 receptor (PVR) 83, 604–605 recombinant 619 recombination of vaccine strain with enterovirus 71 replication 605–606 shedding 617, 619 structure 602, 602 wild-type vs vaccine strains 617 see also enteroviruses; poliomyelitis polyarthritis, alphaviruses associated 648–656 polyethylene glycol (PEG) 300 polyethylene glycol (PEG)-IFN see under interferon polymerase chain reaction (PCR) 1, 3, 8–13 automation, HSV detection 106–107 clinical specimen preparation commercial assays 9–10, 10 consensus, emerging infections 73 contamination 12–13 controls (positive and negative) 12–13, 13 1004 polymerase chain reaction (PCR) (contd.) conventional product, detection dUTP use 13 false-negative results 9, 12 inhibitors in situ, HSV 107 multiplex 9, 10, 12 HPIV 427 HSV 106 micro-bead suspension array 15 physical organization of laboratory 13 primers 9, 11 principle 8, quantification 9–10, 10, 12, 17 quantitative competitive (qcPCR) random primer 73 real-time 10–12, 11, 12 adenoviruses 479–480 advantages/disadvantages 12 HSV 106 influenza virus 394 KSHV 262 noroviruses 55 orthopoxviruses 633, 634 respiratory virus infections 58 reverse-transcription see reverse transcription PCR (RT-PCR) sensitivity 12 specificity 10 viral antigen detection polymerase slippage, HPIV 415–416 Polyomaviridae 823 Polyomavirus new/emerging viruses 74 physical characteristics 50 polyomavirus-associated nephropathy (PVAN) 838 diagnosis 844–845 treatment 848 polyomaviruses see human polyomaviruses Pongola virus 702, 707–708 population increases, emerging infections and 71 porcine endogenous virus (PERV) 872 porcine enteric calicivirus (PEC) 359 porcine enteric transmissible gastroenteritis virus 518 Porpoise morbillivirus (PMV) 535 positive predictive value 16 posterior root ganglia, latent VZV infections 141, 146 post-exposure risk assessment, blood-borne viruses, in HCWs 34, 34–35 post-herpetic neuralgia (PHN), VZV 133, 139, 147 post-poliomyelitis syndrome 610 post-transplant lymphoproliferative disease (PTLD) 216–217 post-vaccinal encephalomyelitis (PVE), rabies vs 791 post-vaccinial encephalitis 634 postviral fatigue syndrome see chronic fatigue syndrome Powassan virus 673, 695 Poxviridae 625 Subject Index poxviruses 625–642 antigens 638 A-type inclusions 627 B-type inclusions 632 cell-associated virion (CEV) 627 classification 625 diagnosis 632–634, 637–638 extracellular enveloped virus (EEV) 626 intracellular enveloped virion (IEV) 627 intracellular mature virus (IMV) 626 lateral bodies 625–626, 627 molluscum contagiosum due to 636–637 mRNA and transcription 627 orthopoxvirus infections 627–635 parapoxvirus infections 635–636 pathogenic for humans 626 phylogenetic relationships 626 physical characteristic/stability 638 replication 626–627, 630 structure/morphology 625–626, 627 tanapox 637 see also orthopoxviruses; smallpox pradefovir mesylate, hepatitis B 305 pRb (retinoblastoma protein) inactivation in KSHV infection 257, 258 JC virus TAg interference 842 repression in HPV infections 810 prediction of viral infections, by molecular techniques 16–17 pre-emptive therapy adenovirus infections 482 CMV infection 186, 189, 189–190 pregabalin, herpes zoster pain 153 pregnancy aciclovir 152 BK polyomavirus 845 CMV infection see cytomegalovirus (CMV) infection herpes zoster 147 HPV infection and genital warts 817 HSV infections 126 infectious mononucleosis 209 influenza 390–391 JC virus (JCV) 837 Lassa fever 749 Marburg or Ebola haemorrhagic fever 764, 765 measles vaccine contraindicated 554 mumps 597 parvovirus B19 infection 58, 862 rashes in 21 rubella (infection) see rubella rubella vaccination 582, 582–583 varicella (chickenpox) 141, 145–146, 155 varicella zoster immune globulin (VZIG) 155 VZV reactivation 53 yellow fever vaccine 678 prenatal diagnosis, rubella 578, 580 prenylation inhibitors, hepatitis D 309 pre-programmed cellular suicide 84 primate foamy virus (PFV) 871 primates Chikungunya virus (CHIKV) 650–651 filovirus infections 755, 756–761, 763, 767–768 hepatitis E virus 280–281 HIV origin 897–898 KSHV origin and related viruses 245–246 monkeypox 72 new/emerging viruses 72, 76 rhinovirus infections 493 Rift Valley fever virus 716 rubella virus infection 565 TTV infections 327 as virus vectors 76 primate T-cell lymphotropic virus (PTLV) 876, 883 prion diseases 939–968 acquired 949, 950, 952–957, 960 see also kuru; variant Creutzfeldt–Jakob disease (vCJD) aetiology and epidemiology 948–949 animal 939, 947 clinical features and diagnosis 949–959, 950 human 939, 948–949 iatrogenic see Creutzfeldt–Jakob disease (CJD) incubation period 948–949 inherited 949, 950, 957–959 initiation/entry route 947 lesion profiles 943 lymphoreticular tissue 946, 947 molecular diagnosis 959–960 neuronal cell death 945 pathogenesis 946–947 pre-symptomatic/antenatal testing 960 prevention and public health 960–961 PRION-1 trial 961 prognosis and treatment 961 sporadic 949–952, 950, 959 see also Creutzfeldt–Jakob disease (CJD) prion protein (PrP) 940 β-sheet state 942 conserved genes 946 copper metabolism role 940, 944 folding 940, 941, 942, 942 gene see PRNP glycosylation 940, 941, 944 mice lacking (Prnp 0/0 ) 943, 945 monoclonal antibodies 961 neuronal signalling role 943 neurotoxicity mechanism 945 normal cellular function 943 octapeptide repeat insertion (OPRI) 957, 959 PrP OPRI 959 PrP27−30 940 PrP102L 957 PrPA117V 957 PrPC 940 apoptosis role 945 conversion to PrPSc 940, 941, 952 destabilization, diseases 941 expression interference 961 minor conformations 941 molecules binding, CJD treatment 961 N-/C-terminal regions 940 structure 940–941 PrPD178N 957–958 PrPE200K mutation 958–959 PrPL 945 Subject Index PrPSc 940 elevated in mice 945 experimental formation 941–942 in follicular dendritic cells 947 formation 941 glycoforms 944 human types 943–944 sporadic CJD 948, 952 structure 941 subcellular localization 942 tonsillar 960–961 transmission 944, 960–961 types 1–4 952, 957 vCJD 952, 955 recombinant, bacterial expression 942–943 self-propagation 941–942, 942, 946 single polypeptide/different phenotypes 944 species, differences 945–946 structures 940–943, 941 transgenic mice expressing hamster PrP 946 transgenic mice expressing human PrP 952, 957 transmission 944 prions definition 940 entry route 947 molecular strain typing 944, 944, 952 neuro-invasion 947 occupational risks 961 protein-only hypothesis 940, 942, 943, 944 Sc237 hamster 945, 946 species barrier 945–946, 949 crossing 946 species-strain barrier 946 strains 943–945 structural biology 940–943 transmissible mink encephalopathy 943 hyper (HY) and drowsy (DY) 943 transmission barrier 946 unified hypothesis 943 yeast 944 PRNP gene 948 129 MM 948, 949, 956 129 MV 956 analysis, in CJD 949, 950, 951, 957, 959 carriers of mutations 960 coding mutations 940, 952 codon 129 genotype 952, 960 kuru 952 sporadic CJD 952 codon 129 heterozygosity 948, 952 conserved 946 kuru 952–953 mutations absent in vCJD 948 mutations and polymorphisms 957–959, 958 sporadic CJD 948 see also prion protein (PrP) progressive multifocal leukoencephalopathy (PML) 823, 831, 840–841 astrocytes 841, 842, 843, 845 biopsy 843 cellular immune response 846–847 clinical features and risk factors 840 definition scheme 844 diagnosis 843, 844 duration/progression and outcome 841 HAART effect 840, 841, 847 in HIV infection 840, 841, 844, 914 IgM antibodies 846 immune response in 846 immunocompromised patients 835 JC virus spread to CNS 835 JCV viruria 837 pathogenesis/lesion development 840, 841 transcriptional control region (TCR) type 833 treatment 847 promoter-insertion hypothesis 307 Prospect Hill virus 704, 722 protease inhibitors (PIs) 921, 925–928 D30N and L90M mutants 920 first-generation 926 HIV infection 903, 917 mechanism of action 925 mutations/resistance 920 new drugs 926 resistance/mutations 926, 926, 927 protective antigens 85–86 protein phosphatase 2A (PP2A) 842 proteinuria, haemorrhagic fever with renal syndrome (HFRS) 724 PrP see prion protein (PrP) pseudocowpox 635 host, distribution 626 ptosis, herpes zoster 147 pulmonary oedema, smallpox 629 ‘pulvinar sign’, vCJD 955 Punta Toro virus 703, 711–712 pure red cell aplasia, parvovirus B19V infection 862–863 Puumala virus 704, 722, 724, 725 Q quadriparesis, rabies 790 qualitative detection of viruses 16 quality control, molecular amplification techniques 15, 16 quasispecies, viral 18, 523 quinacrine, CJD 961 R rabies 777–806 aerophobia 788 alternative names 777 animals 798 bats 782, 783, 787, 801 clinical features 787 control 800–801 diagnosis 795 dogs 777, 782, 783, 787, 796, 801 foxes 781, 782, 801 immune response 785 incubation period 787 raccoons 782, 801 recovery and chronic infection 787, 791–792 treatment 796 vampire bats 783, 787, 790, 801 antibodies 1005 detection methods 795 IgM and IgG 785, 795 neutralizing 785–786 autonomic stimulation 789 biochemical tests 791 bites 781, 783, 786, 787–788, 798 management after 800 brain biopsy 795, 797 brain infection process 784 cellular immune response 785 children 797 ‘classical’ 788 clinical diagnosis 791 clinical features 787–794 complications 789, 790 countries/areas free of 780, 781 diagnosis 794, 794–795 immunofluorescence 794, 795 intra vitam 794–795 post-mortem 795 differential diagnosis 790, 790–791 ‘early death’ phenomenon 785 encephalitis/encephalomyelitis clinical features 788 diagnosis 794 immune response 785 pathology 796–797 enzootic infection 781, 801 epidemiology/epizootiology 781–783 furious (agitated) 788–789, 789 differential diagnosis 790 global distribution 780, 781–783 haematological tests 791 history 777–778 hydrophobia 777, 788–789, 790 pathophysiology 789 immune response 785 assays 786 immunoglobulin (RIG) 798, 799, 800 immunology 785–786 immunosuppressive effect of 785 incidence 783 incubation period 785, 787–788 infection routes 786, 798 interferon-α effect 785 management 796 after bites 800 meningoencephalomyelitis 796 mortality 789, 796 Negri bodies 778, 779, 784, 796 neurological investigations 791 paralytic (dumb) 788, 789–790 differential diagnosis 790, 791 outbreak (Trinidad) 790 pathogenesis 780, 783–785 pathology 796–797 phobia 788, 790 pneumomediastinum 789 prodromal symptoms 788 prophylaxis 797–800 recovery 791–792 respiratory features 789 spasms 788, 789 sylvatic (wildlife), control 801 transmission 781, 786, 798 1006 rabies (contd.) aerosol 786 bites 798 human to human 786 routes 786 see also rabies, bites transplacental 786 vaccine-induced 786 vaccines 797–800 for animals 801 animal species/behaviour and 798 antigen stability 781 booster doses 797–798, 800 developing countries 800 duck embryo 791–792 efficacy against rabies-related viruses 799–800 eight-site intradermal regimen 800 exposure confirmation 798 ‘failures’ 799 four-site intradermal regimen 800 historical aspects 777–778 human diploid cell (HDCV) 778, 797, 800 immune response to 785–786 infection site affecting 798 Pasteur’s 777, 778 post-exposure 796, 797, 798–800 post-exposure, decision to use 798 post-exposure, efficacy 799 post-exposure in vaccinated patients 799 pre-exposure 796, 797–798 primary post-exposure 799 purified chick embryo cell (PCEC) 792, 797 purified Vero cell (PVRV) 792, 797 recombinant 801 recovery after 791–792 regimens 796, 797, 799 Semple brain tissue 777, 800 side effects 800 two-site intradermal regimen 800 viraemia 784 wound treatment 799 rabies-related viruses human infections 792–793 vaccine efficacy 799–800 see also European bat lyssaviruses (EBLV) rabies virus 779 antigens 784, 785 detection 794–795 assembly, maturation and release 781, 785 attachment and fusion 780, 783–784 brain infection 784 centrifugal spread from brain 784–785 classification 778 genome (negative-sense ssRNA) 778 G (glycoprotein) protein 778, 780 host gene expression downregulated 784 inactivation 781 infection routes 786, 798 intracellular transport 780 isolation/identification 794–795 L protein (RNA polymerase) 778, 780 M (matrix) protein 778, 780 N (nucleoprotein) protein 778, 785 Subject Index P (phosphoprotein) protein 778, 780, 784 replication 780–781 inhibition by interferon-α 785 sites 784–785 RNA polymerase 778, 780 RNP complex 778, 780–781 shedding 784 stability 781 structure 778, 779, 780 transmission see rabies, transmission transport to brain 784 vectors/reservoirs 781–783 raccoons, rabies 782, 801 raltegravir (RAL) 922, 929 Ramsay–Hunt syndrome 146 RANTES 417 rapamycin, KSHV infection 263 rapid immunofluorescent focus inhibition test (RIFFIT), rabies 786 rash(es) Barmah Forest virus (BFV) 655 Chikungunya virus infection 651 Crimean–Congo haemorrhagic fever 719 EBV infection 209 HHV-6 infections 232 human parvovirus B19 (B19V) 856, 860, 860 Lassa fever 748 measles 543, 544, 547 monkeypox 630 o’nyong-nyong virus 652 in pregnancy 21 Ross River virus infection 653 rubella 566 congenital rubella syndrome (CRS) 572, 573, 574 rubelliform, enteroviruses causing 613 serological testing 22 Sindbis virus infection 649 smallpox 143, 628 varicella (chickenpox) 143–144, 146 West Nile fever 690 reassortment of viruses 71, 86 receptor-destroying enzyme (RDE), HPIV infection 426 recombinant immunoblot assay (RIBA), HCV 273, 311 recombination of viruses 71 HIV 918 KSHV 246 Relenza see zanamivir renal dysfunction, mumps 597 renal haemodialysis blood-borne virus transmission 32 screening assays 20 renal transplant recipients adenovirus infections 476 BK virus infection 837 CMV disease prognosis 169 CMV infection prevention 183–184 Reoviridae 365 reoviruses, acute diarrhoeal disease 365 representational difference analysis (RDA), emerging viruses 73–74 reproductive rates of viruses (Ro) 82, 89 see also basic reproductive rate/number (Ro) respiratory rate, RSV infection 447 respiratory secretions, smallpox 628 respiratory syncytial virus (RSV) 441–461 adsorption 442 antigenic variation 442 classification 441 cp (cold passage)/ts (temperature sensitive) mutants 453, 454 cytopathic changes 450–451 detection see respiratory syncytial virus (RSV) infection, diagnosis discovery 441 gene variants (polymorphisms) 450 genome (negative-sense RNA) 441 glycoproteins (F and G) 441–442 antibodies to 442, 445, 446 monoclonal antibody to F 454 vaccine development 454 isolation 450–451 persistence in environment 49, 444, 455 physical characteristics 50 replication 442 shedding 62, 449 strains A and B 442 structure/morphology 441, 442 transmission 52, 62–63, 443–444 prevention 62 to/by HCWs 444 respiratory syncytial virus (RSV) infection acute complications 448 antibodies 446 detection 452 IgA 445 IgM and IgG 445, 452 maternal 445 neutralizing 442, 445 bronchiolitis 443, 444–445, 445, 446–447, 453 children 441, 443, 446–447, 449 clinical features 446–448 children at increased risk 449 older children/adults 450 primary infection 447–448 co-infections 448 cytopathology 446 diagnosis 63, 450–452 enzyme immunoassays 451 immunofluorescence 4, 451, 451 PCR 451 serologic 451–452 elderly 450 epidemiology 441, 442–444, 447 of HCWs 444 immunity to 445–446 cellular 446 humoral 445–446 innate 445, 446 Th1 and Th2 responses 446, 450 immunocompromised patients 449 incubation period 52, 444 infants 444, 446–447, 448, 449 immunization 454 influenza vs 450 management 63, 452–453 mortality 444 Subject Index neonates 448 nosocomial 62–63, 443–444 prevention 455, 455 otitis media 448 outbreak size 443 passive immunization 454 pathogenesis 444–445, 446 pathology 444–445, 445 pneumonia 446–447 prevention 453–455 infection control 455, 455 repeated 449, 450 seasonal 442, 444 sequelae 449–450 vaccines 446, 453–455 live-virus (cp or ts) 453–454 subunit 453, 454 respiratory tract infections adenoviruses 463, 471, 473–474 enteroviral 613 influenza see influenza parainfluenza viruses see human parainfluenza virus(es) (HPIVs) RSV infections see respiratory syncytial virus (RSV) infection respiratory viruses diagnosis 4, 58 nosocomial infections 58–63 seasonal epidemics 58 Respirovirus 409, 410 Restan virus 702, 710 restriction enzyme analysis (REA), adenoviruses 480 restriction fragment length polymorphism (RFLP), orthopoxviruses 633 retinal necrosis acute HSV 118, 126 VZV 147–148 progressive outer (PORN) 148 rapidly progressive herpetic 148 retinitis CMV 190, 912 varicella 147–148 retinoblastoma protein see pRb (retinoblastoma protein) retinopathy, congenital rubella syndrome (CRS) 570, 574 Retroviridae 870 classification 18 retroviruses 869–873 animal diseases 871 animals/species infected 869 env gene 870 ‘fossil’ infections 870, 872 gag gene 870 gag-pol precursor 870 genera 870, 871 genes 870 genome (ssRNA) 869–870, 870 genome integration 872 human endogenous (HERVs) 872 infections 870–872 long terminal repeats (LTRs) 870 low-level, DNA detection 871 murine 871 pol gene 870 replication 869–870, 870 reverse transcriptase 869 SU protein 870 taxonomy 870, 872 TM protein 870 as vectors for gene therapy 869, 872–873 zoonotic infections 869, 870–872 see also HIV; HTLV reverse genetics technology Ebola virus infections 766, 769 HPIV vaccine development 428 influenza vaccine development 399, 403 measles virus (recombinant) 535 RSV vaccine development 454 reverse transcriptase (RT) 869 discovery 871, 875 reverse transcription nested PCR (RT-nPCR), rubella 577, 578, 580 reverse transcription PCR (RT-PCR) alphaviruses 647 bunyaviruses 705 Chikungunya virus 652 coronaviruses 523, 524 dengue virus 683 EIA with (RT-PCR-EIA), HPIV 427 GBV-C 324, 325 hantaviruses 726 HCV infection 311 HPIV 427 Lassa virus 750 measles 551 noroviruses 55 rabies virus 795 RSV infection 451 reverse vaccinology 85 Reye’s syndrome HPIV causing 424 influenza 390, 396 varicella (chickenpox) and 145 RGD motif adenoviruses 467 KSHV glycoprotein 255 Rhabdoviridae 778 rhesus monkey papillomavirus type 814 Rhesus monkeys, ZEBOV (Ebola Zaire virus) 767 rhesus rotavirus (RRV) 343 rheumatoid arthritis, parvovirus B19V role 861 rhinoviruses 489–510 2A protease and 3C protease 492 antigenicity 490–491 canyon 490, 491 ‘canyon hypothesis’ 491 capsid 489–490 cell culture 498 cell lines, growth 495 cytopathic effects 493, 498–499 electron microscopy 490 enteroviruses relationship 489 genome (positive-sense ssRNA) 489, 491, 492 groups A and B 489, 496 history/discovery 489 1007 host range 493 HRV-2 490 HRV-14 603 HRV-87 489, 496 incubation period 493 internal ribosome entry site (IRES) 491 isolation 498–499 major and minor groups 489, 491 mRNA 491 persistence in environment 49, 492, 493 physical characteristics 50, 492 ‘pocket’ and ‘pocket factor’ 490 proteins 490, 490 receptors 491 replication 491–492, 493, 498 RNA polymerase 491 serotypes 496 shedding 492 structure 489–492, 490 taxonomy 489 transgenic murine model 493 translation 492 transmission 492–493, 496 as vectors 491 VP1-VP4 490, 501 rhinovirus infections antibodies IgG and IgA 495 neutralizing 499 asthma exacerbation 495, 497–498 atopy and 496 bronchitis, bronchiolitis and pneumonia 498 cellular immunity 495–496 children 496, 497 chronic 493 clinical features 497–498, 498 cold temperature exposure and 496 common colds 489, 496–497 complications 497–498 in COPD 492, 495, 498 cytokines/kinins and chemokines produced 494, 495 diagnosis 498–499 ELISA 499 haemagglutination inhibition (HI) 499 nucleic acid detection 499, 500 PCR 499, 500 serology 499 virus isolation 498–499 epidemiology 496–497 immunity/immune response 495–496 immunocompromised people 497 incubation period 497 morbidity 497 nasal secretions 493–494 pathogenesis 493–495, 494 prevention 500–502 primary site of infection 493 treatment 494, 500–502, 501 targets/strategies 492, 494, 495, 501 vaccine decavalent 500 obstacle to development 500 viraemia 493 1008 ribavirin 314 adenovirus infection 481, 482 Bolivian haemorrhagic fever 747–748 coronavirus infections and SARS 526 Crimean–Congo haemorrhagic fever 720 hepatitis C 314–315 HPIV infection 429 influenza 396, 398 Lassa fever 750 measles 552 mechanism of action 398, 452, 482 RSV infection 452 side effects 315, 398, 452, 482, 750 structure 397 riboprobes 14 Rickettsia conorii infection 720 Rift Valley fever virus, and infection 701, 703, 712–717 abortion 716 antibodies 717 clinical features 713, 714, 715–716 detection/identification 705 diagnosis and investigations 716–717 differential diagnosis 717 Egypt epidemics 713–714, 715 encephalitis 715–716 epidemiology 712–714 geographical distribution 712 haemorrhagic form 715 haemostatic derangement 715, 716 infection route 715 Kenya outbreaks 712, 714 mosquito vectors 712–713, 714 ocular disease 715 outbreaks and epidemics 712, 713 pathogenesis of infection 716 pathology 716, 717 Saudi Arabia and Yemen 714 South Africa/Zimbabwe 712 transmission cycles 713 treatment 716 vaccine 717 rimantadine influenza 60, 396–398 side effects 398 structure 397 Rinderpest virus (RPV) 535 ring sores 635 Rio Bravo virus 672, 673 Rio Mamore virus 704 Rio Segundo virus 704 ritonavir boosting, protease inhibitors 926 HIV infection 925, 926 rituximab 217 RNA editing, HPIV 415–416 RNA interference, filovirus infection therapy 766 RNA replicons, HPIV vaccine development 429 RNA viruses nucleic acid sequence-based amplification 13–14 rapid evolution 881 Ro (basic reproductive rate) see basic reproductive rate/number (Ro) Subject Index Rocio virus 669, 673, 678–679 rodents arenaviruses 733, 734, 742 LCMV 741–742, 745 control, Lassa fever control 750 cowpox transmission 631, 632 Ebola (Zaire) virus model 767 filovirus infections 767, 770 hantavirus transmission 73, 75, 721–722, 723 monkeypox reservoir 72 persistent virus infections (arenaviruses) 733, 742 roseola infantum (exanthem subitum) 232 Roseolovirus 224 roseoloviruses 223–244 see also human herpesvirus (HHV-6); human herpesvirus (HHV-7) Ross River virus (RRV), and infection 644, 644, 653–654 clinical disease 653–654 diagnosis and isolation 654 epidemiology and host range 653 pathogenesis 654 rubella differential diagnosis 567 vaccine 654 rotaviruses 337–353 antibodies 338, 342, 343 classification 337–338 double-layered particles (DLPs) 338, 339, 343 electron microscopy 338, 343, 356 G1-G4 types 345 G9 type 345 G and P types 338, 343–344 gene–protein assignments 340–341 genes 340–341 genome (dsRNA) 337, 339 genomic drift/shift 345 groups 337–338 groups A, B, and C 345 infections in children 343 clinical features and diagnosis 343–344, 355 epidemiology 337, 344–345 immune response and IgA 343 incubation period 52, 343 mortality 337, 343 nosocomial 56, 345 pathogenesis 342, 342–343 seasonal 56 treatment 344, 344 NSP4 (enterotoxin) 341, 342 nursery strains 343 persistence in environment 49, 56 proteins (VP1-VP3) 337, 339, 340–341 replication 338–339, 342 structure 337, 338, 339 transmission 52, 338 triple-layered particles (TLPs) 338 vaccines 56, 85, 345–346 intussusception cases 344, 345 lamb strain LLR (live attenuated) 346 live attenuated 345–346 monovalent 346 pentavalent 346 tetravalent 345 viroplasms 339 VP4 and VP7 338, 340, 341 Royal Free disease see chronic fatigue syndrome RT-PCR see reverse transcription PCR (RT-PCR) rubella 561–592 antibodies 561, 565, 568, 569 detection 576–577 loss in congenital rubella 579–580 post-vaccination 580 see also rubella, IgG; rubella, IgM antibody screening tests 576 clinical features 566 complications 566–567 congenital see congenital rubella syndrome (CRS) developing countries 566, 585–586, 586 diagnosis/laboratory techniques 576–580 congenitally acquired infection 578–580 enzyme immunoassay (EIA) 576 oral fluid/dried blood spots 577 prenatal 578, 580 serological 576–577, 579 serological in women exposed to RV 577, 578 serological in women with rubella-like illness 577–578 virus detection 577, 579 differential diagnosis 567, 567–568 epidemiology 565–566 fetal infection after reinfection of mother 569 see also congenital rubella syndrome (CRS) global distribution 564, 565–566 haemagglutination inhibition test 561, 579–580 HCW susceptibility 46 historical events 561, 562 IgA, after vaccination 580 IgG 569, 575, 577, 578 after vaccination 580 avidity 576–577 persistence in infant 579 IgG1, detection 579 IgM 568, 569, 570, 575, 577, 578 after vaccination 580 detection 576, 579 immune response 565, 568, 568–569, 570 immunity 569, 580–581 immunoglobulin (therapeutic) 578 immunosuppression associated 568 incubation period 52, 561 isolation of infants 576 neonatal 570 nosocomial 46–47 pandemics 566 pathogenesis 566 placental infection and 569 post-infectious encephalitis 567 postnatally acquired infection 565–569 pre-conceptual 570–571 Subject Index in pregnancy 46, 561 after first trimester 570 diagnosis/laboratory tests 577–578 first trimester 562, 569, 570 gestational age and 570, 571 management 578 see also congenital rubella syndrome (CRS) prenatal diagnosis 578, 580 rash 566 reinfection 569, 581 diagnosis 578 risk to fetus 570–571 vaccination 580–586 adverse reactions 581 contraindications 581–582 developing countries 585–586, 586 efficacy and reinfection 581 Europe 584–585 failures 581 immune response 580–581 joint disease after 567, 581 low/intermediate uptake rates 584, 586 monitoring efficacy, seroprevalence 583 other vaccines with 582 pregnancy 582, 582, 582–583 prevalence reduction by 83, 583, 584, 584, 585 programmes 583–586 required coverage 82 in UK 583–584, 584 in USA 583 WHO recommendations 585, 585–586 vaccines attenuated, development 580 RA27/3 strain 564, 565, 580 viraemia 568 virological features, clinical feature correlation 568, 568–569 rubella virus (RV) alphaviruses similarity 562 in amniotic fluid 580 antigenic characteristics 565 assembly and release 564–565 attachment and infection process 564 cell culture 561 clades and genotypes 564 classification 562 C protein 564 in CSF 570 cytopathic effect 565, 577 detection 577 E1 and E2 proteins 562, 564, 565 excretion 569–570, 581 in fetal blood 580 G+C content of RNA 562 genetic variation 562, 564 genome (positive-sense ssRNA) 562, 563 global distribution 564 growth in cell culture 565 interference assay 561 nonstructural proteins 562, 563 origin 71 p150 and p90 564 pathogenicity for animals 565 persistence 569–570 physical characteristics 51, 565 polyprotein (p200) 564 replication 564–565 stability 565 structural proteins 563 structure 562 subgenomic RNA 564 teratogenicity 565, 569 transcription 563 translation 563 transmission 52, 566 vaccine strain (RA27/3) 564, 565, 580 Rubivirus 562 Rubulavirus 410, 410, 593 ‘rule of six’ replication 415, 535 Russian spring summer encephalitis virus (RSSEV) 673, 693 S Saaremaa virus 704 Sabi´a virus 734, 751 sacral ganglia, herpes zoster 146 St Louis encephalitis see St Louis encephalitis (under St) saliva CMV in 167, 176 EBV in 206, 215 HHV-6 in 228, 229 HIV in, testing 907 KSHV in 250, 255 samples/specimens 20 antibody detection for PCR storage 20 viral antigen detection Sandfly fever Naples virus 703, 711 Sandfly fever Sicilian virus 703, 711 sandfly fever viruses 700, 703, 711 Sangassou virus 704 SAP (signalling lymphocytic activation molecule associated protein) 216 sapoviruses (SaVs) 355, 358–363 antibodies 361–362, 362 classification 359 diversity and evolution 362 epidemiology 361–362 by age 357 patterns 361–362 gastroenteritis clinical course/features 358, 361 pathogenesis 360 prevention 363 genome 359, 360 immune response 361 laboratory diagnosis 360–361 replication and cell culture 359–360 structure 356, 359 transmission routes 362 saquinavir, HIV infection 926, 927 SARS 43 asymptomatic 520 clinical features 365, 521–522 diagnosis 523 1009 elderly 522 emergence 519 epidemiology 519–520 first cases 71, 519 Hong Kong outbreak 61, 62, 71 incubation period 521 mortality 71, 522 nosocomial infections 61–62 prevention/precautions 62 WHO recommendations 62 passive immunization 525–526 pathogenesis and pathology 523 pneumonia 521–522, 526 re-emergence 525 ‘super-spreading incidents’ 519, 520 susceptibility, genetic polymorphisms 523 transmission of virus 519–520 treatment 526 vaccine 525 see also SARS-CoV SARS associated virus 7, persistence in environment 49 SARS-CoV 511 antigenic structure 517 classification 511 continued circulation, evidence lacking 520 detection/identification 74, 523 genome organization 516 host range and civet SARS-like virus relation 518–519 isolation and culture 524 origin 76–77 persistence in environment 62 receptor (ACE2) 518 re-emergence 61 spike protein, monoclonals to 525–526 transmission 61–62, 519–520 aerosol and droplets 520 see also SARS SARS-like coronavirus in bats 519 in civets 518, 519, 520, 525 SaV see sapoviruses (SaVs) scabies, Norwegian, HTLV-1 and 885 SCH 503034, hepatitis C treatment 316 schizophrenia 390 SCID-hu mouse, VZV infection model 136, 140 scrapie 939, 947 atypical 947 screening assays 20, 20 ‘scrum pox’ 116 seasonal infections common colds 496 HPIV infections 422, 422 influenza 388, 388–389, 391 rotaviruses 56 RSV 442, 444 seizures see convulsions ‘self’ antigens, tolerance 743–744 self-fluorescing amplicon concept, PCR 10, 12 Semliki Forest virus (SFV) 644, 644, 646, 661–662 Semliki Forest virus complex origins and distribution 650 viruses included 644 1010 Sendai virus (SeV) 410, 414–415 HPIV vaccine and 428 replication 414–415 sensitivity of tests 15, 16 sensory nerves, VZV latency 141, 146, 147 Seoul virus 704, 722, 723, 725 Sepik virus 673 sepsis, varicella associated 144 septic shock, smallpox 629 serology 3–8 advantages/disadvantages antibody detection 5–7 first-line tests 22 interpretation 7–8 nonvirological with virological 20 tests not indicated, conditions 21 viral antigen detection 3–5 serum neutralization (SN), adenoviruses 480 severe acute respiratory disease see SARS severe immunodeficiency (SCID), norovirus/sapovirus gastrointestinal infections 361 sexual transmission adenoviruses 477 CMV 167, 168 EBV 206 HBV 283 HIV 899, 930, 931 HPV 813, 814 HSV 103, 104 HTLV 883–884 KSHV (HHV-8) 250–251 SH2 (src-homology) domain 216 shellfish, hepatitis A transmission 276 shell vial assay VZV 149 shingles see herpes zoster ‘shipyard eye’ 474 shock, Ebola haemorrhagic fever 769 Shokwe virus 702, 707 Shuni virus 702, 711 Siadenovirus 464 sialic acid analogues, HPIV infection treatment 429 sialic acid receptors adenoviruses 467 BKV 825 influenza virus 378, 379, 386 JC virus 824 mumps virus 594 parainfluenza viruses 411–412, 417 sialoglycoproteins, HPIV binding 412, 414 Siberian tick-borne encephalitis virus (S-TBEV) 692 sickle cell disease, parvovirus B19V associated aplastic crisis 861 signalling, KSHV proteins 260 signal transducer and activation of transcription (STAT1) 357 simian haemorrhagic fever virus (SHFV), Ebola Reston co-infection 761 simian immunodeficiency virus (SIV) 931, 932 SIVcpz 897 simian T-lymphotropic viruses (STLV-1, STLV-2) 76, 876, 880 Subject Index simian virus (SV5) 410, 414 Simplexvirus 95, 96 Sindbis-like virus 659 Sindbis virus (SINV) 644, 644, 648–649 infection, rubella differential diagnosis 567 single radial haemolysis (SRH) technique, influenza 395 Sin Nombre-like viruses 723 Sin Nombre virus 73, 704, 722 see also hantaviruses SIV/HIV chimaera 931 sixth disease (exanthem subitum) 232 Sjăogrens syndrome 886 skin biopsy, rabies diagnosis 794, 795 skin infections, HSV 116, 127 SLAM (signalling lymphocytic activation molecule) see CD150 (SLAM) slapped cheek disease (fifth disease) 856, 859–860 ‘slim’ disease 899 slow virus infection 939 see also prion diseases small anellovirus (SAV) 326 genome 326, 327 small interfering RNA (siRNA), coronavirus infection treatment 526 smallpox 627–630 animal models and pathogenesis 629 bioterrorism and 625 cause of death 629 classic (ordinary) 628 clinical features and lesions 628–629 diagnosis 632 eradication 81–82, 91, 628 flat-type 628 forms and presentations 628–629 Global Eradication Programme 634 haemorrhagic-type 628 host, distribution 626 immunity 629 incubation period 628 modified-type 628–629 Rao classification 628–629 rash 628 varicella vs 143 sine eruptione 629 transmission 627–628 vaccination 634–635 adverse events and encephalitis 634 cost-effectiveness 91, 91 discovery, cowpox use 81 mandatory 90 modified vaccinia ankara (MVA) strain 634–635 strains 634 Snow Mountain strain of NoV 361 Snowshoe hare virus 702, 708–709 solid organ transplant recipients see transplantation (organ/tissue) recipients sorivudine (BVaraU), herpes zoster 152–153 ‘source drying’, concept 89 spasms, rabies 788, 789 specificity of tests 15, 16 specimens see samples/specimens spindle cells, endothelial cell-derived, KSHV infection 252 splenic rupture, EBV infection 209 Spondweni virus 673 Spumavirinae 870 spumaviruses 871, 872 squamous cell carcinoma (SCC), epidermodysplasia verruciformis and 813 SRSV (small round structure virus) 52 ST-246, vaccinia vaccinatum treatment 635 Staphylococcus aureus methicillin-resistant 23 pneumonia in influenza 390 ‘starry sky’ appearance 212, 213 STAT1, interferon response, HPIV infections 419–420 STAT2, interferon response, HPIV infection 420 stem cell transplant patients HTLV-1 infection treatment 890 screening assays before transplant 20 see also haematopoietic stem cell transplant (HSCT) recipients ‘sterilizing immunity’ 84 HSV 112 steroid therapy HPIV infection 429 infectious mononucleosis 211 see also corticosteroids Stevens-Johnson syndrome 117 St Louis encephalitis 687–688 control 688 diagnosis 687–688 epidemiology and clinical features 687 St Louis encephalitis virus (SLEV) 673, 687–688 vectors, host range 687 strand displacement amplification (SDA) 14 Strongyloides stercoralis 885–886 subacute sclerosing panencephalitis (SSPE) 544–545 clinical course/features 544 diagnosis 552 immunological aspects 550–551 pathogenesis 549–551, 550 risk factors 544 treatment 552 virological aspects 549–550 see also measles subacute spongiform encephalopathies see prion diseases subconjunctival haemorrhages 613 subtypes/clades cell tropism 897–898 circulating recombinant forms (CRFs) 897 sudden infant death syndrome (SIDS), influenza 391 supplementary immunization activities (SIAs), polio 618 surgeons HBV infection 37 HCV infection 37 HIV infection 38 survivin (apoptosis regulator) 259, 825, 840 sustained viral response (SVP) 17–18 swine see pigs (swine) Subject Index SYBR green 9, 10 syncytium HIV-1 897, 901 HPIVs 413, 417 HTLV-1 causing 876 RSV infection 442 syphilis, blood donation testing 31 systemic lupus erythematosus (SLE), TTV infection and 330 T Tacaiuma virus 702, 710 Tacaribe virus 734, 734 antibodies 742 infection, therapy 747 Tahyna virus 702, 709 tamarins, GVB-C 321, 322 Tamiflu see oseltamivir tanapox 637 host, distribution 626 Tanganya virus 704 Taq DNA polymerase 10 TaqMan oligoprobes 10, 11, 683 TATA binding protein CMV transcription 163 HPV transcription 810 TATA box, JC virus 827, 832 Tataguine virus 703, 726 T cells see T lymphocytes telbivudine, hepatitis B 303 telithromycin, rhinovirus infections 500 tenofovir disoproxil fumarate (TDF) hepatitis B 303–304 HIV infection 922, 923, 931 side effects 304 Tensaw virus 702, 707 teschoviruses 601 tetanus, prevalence reduction by vaccination 83 tethrin 901 Thailand virus 704, 722 thoracic ganglia, latent VZV infections 141, 146 Thottapalyam virus 704, 723 throat, sore EBV infection 208, 211 filovirus (Marburg/Ebola) infections 764 thrombocytopenia Ebola haemorrhagic fever 765 rubella 567 thrombocytopenic purpura, congenital rubella syndrome 573 thymidine kinase (TK) CMV 165 HSV 108, 109, 111 VZV, mutants 153 thymosin, hepatitis B therapy 305 thyroid autoantibodies 575 tickbite fever 720 tick-borne bunyaviruses 701, 703 tick-borne encephalitis 691–694 control 693–694 diagnosis 693 epidemiology 692–693 mortality 692 vaccines 694 ‘tick-borne encephalitis serocomplex’ 691 tick-borne encephalitis virus (TBEV) 691–694 characteristics 691–692 detection, monoclonal antibodies 692 distribution and vector 673, 691, 692 E protein 671 subtypes 691, 692 transmission 692 tick-borne flaviviruses 672 ticks bunyavirus transmission 701, 703 CCHF virus 718 control strategies 720 time-resolved fluorescence assay (TRFA) Tinaroo virus 702, 710 tipranavir, HIV infection 927–928 tissue factor (TF) expression, Ebola haemorrhagic fever 769 T lymphocytes activation, X-linked lymphoproliferative syndrome 216 adenovirus infections 470 apoptosis Ebola haemorrhagic fever 769 rabies 784, 785 smallpox 629 cytotoxic see CD8+ cells; cytotoxic T cells dengue haemorrhagic fever 683 helper HTLV-1 infection 887–888 see also CD4+ cells; Th1 and Th2 (below) HHV-6A and HHV-6B tropism 225 HHV-7 tropism 226 immunosuppression/‘tolerance’, LCMV infections 742, 743–744 Japanese encephalitis virus tropism 685 rhinovirus infection 495–496 RSV infections 446, 450 Th1 measles 547 RSV infections 446 Th2 measles 547 RSV infections 446, 450 vaccine-mediated protection from SARS 525 see also cell-mediated immunity (CMI) TMC278, HIV infection 925 Togaviridae 562, 643, 669 see also alphaviruses Togavirus, physical characteristics 51 Toll-like receptors (TLRs) 83, 84 measles 547 rhinovirus infections 496 RSV infection 445 tongue tremor 746, 747 tonsillar biopsy, vCJD 955–956, 956 Topografov virus 704, 722 topoisomerase II, induced by CMV 165 TORCH screen 21, 21 toroviruses 511–531 antigenic structure 517 assembly of virions 516 classification 511 1011 enteric 514 enteric infections 522 genome organization 516, 516 HE protein 512, 514, 517 proteins 512, 514 structure and electron microscopy 511–512, 514, 515 transcription and replication 514–516, 516 see also coronaviruses Torque teno virus (TTV) see TTV Torres bodies 677 Toscana virus 703, 711 toxic epidermal necrolysis 117 tracheal obstruction, EBV infection 209 tracheobronchitis, influenza 386, 389 trade, dengue transmission 681 trailer complementary (TrC) promoter, HPIV 415 transcriptional activators CMV 831 hepatitis B virus 286, 307 HTLV-1, Tax 831, 886 human polyomaviruses (JC virus; BKV) 830, 831 LANA-1 in KSHV infection 257 transcription regulatory sequence (TRS), coronaviruses 515 transforming growth factor (TGF-β), JC virus (JCV) 828 transfusion transmitted infections (TTIs) incidence and mortality 31 see also blood/blood-product transfusions ‘transfusion-transmitted virus’ see TTV α-trans-inducing factor (α-TIF) 98 transmissible gastroenteritis coronavirus (TGEV) 513, 525 receptors 517 transmissible mink encephalopathy (TME) 939, 943, 947 transmissible spongiform encephalopathies see prion diseases transmission of viruses blood/blood products see blood-borne viruses body fluids associated, precautions 29 genetic analysis 18 nosocomial see nosocomial infections/transmission prediction, molecular techniques 18 routes (respiratory/faeco-oral) 43–68 transplantation (organ/tissue) blood-borne virus transmission 32 CMV transmission 168, 168 HHV-6 transmission 230 HTLV transmission 891 KSHV transmission 251, 252 LCMV transmission 745 transplantation (organ/tissue) recipients adenovirus infections 476 antibody detection tests HHV-6 infection 235 HPIV infections 424 KSHV infection 252, 254 RSV infection 449 see also individual organ transplants 1012 travellers arenavirus infections 740 dengue fever 681 emerging infections and 71 flavivirus infections 670 HBV vaccination 294 hepatitis A virus vaccine 279–280 Japanese encephalitis 686 yellow fever vaccine 678 travellers’ diarrhoea, Aichi virus associated 364 tricyclic antidepressants, herpes zoster pain 153 trigeminal ganglia, latent VZV infections 141, 146 Trocara virus (TROCV) 644 TTMV see TTV-like mini virus (TTMV) TTV 73–74, 321, 325–332, 326 classification 325–326 detection and PCR 333 diseases associated 330 genome (antisense ssDNA) 321, 325, 326, 327, 331, 332, 332 ORFs 329, 331, 331 genotype Ia 329, 330 HCV co-infection 330 HIV co-infection 330 HPV co-infection 330 in lower animals 327, 329, 329 in nonhuman primates 327 pathogenicity 329, 330 pathology 329 PCR 333 phylogenic analysis 328 prevalence 321 proteins 331–332 replication 329, 330 target cells 329–330 transcriptional control 331 transmission routes 329, 330 TTV group of viruses 326–327 TT virus (TTV) see TTV TTV-like mini virus (TTMV) 325–326, 326 genome 326, 327 viral load in HIV infection 330 tuberculosis HIV infection and 912 HTLV infections and 885 Tula virus 704, 722 tumour necrosis factor-alpha (TNF-α), TNF-308, dengue haemorrhagic fever 683 tumours see cancer; individual tumour types Turlock virus 702, 710 Tzanck cells 148, 149 U Uganda S virus 673 ultrasound scanning, CMV infection 182 Una virus (UNAV) 644, 662 upper respiratory tract infections adenoviruses 471, 472 coronaviruses 520–521 HPIV 420, 423 rhinovirus 493 RSV infection 448 Subject Index uracil, synthetically-modified pyrimidine bases, HPIV 430 urine adenoviruses 477 BK polyomavirus (BKV) DNA 833, 834, 836–837, 844 CMV detection 175–176 JC virus (JCV) DNA 833, 834–835 USA infection reduction by vaccination 83 mortality of infectious diseases 69, 70 rubella vaccination 583 Usutu virus 673 Uukuniemi group of viruses 700, 703, 717 Uukuvirus 699 uveitis, HTLV-1 885, 891 V vaccination infection reduction by 83 minimum coverage to stop transmission 82, 82 optimal 82 programmes, planning/implementation 89 targeting of specific groups 89 UK programme/service 89 see also vaccinology vaccines activities for market introduction of 88, 88 administration routes 86, 87 adverse events 89 antigen dose 86 cost-effect and cost-saving 91, 91 coverage maintenance 89–90 development historical 85 routes 86 future developments 90 international campaigns and opinions 90 ‘killed’ whole-virion 86 live attenuated 86, 89 non-replicative (inactivated) 86 R&D 86–87, 87 regulatory approval 87 replicative 86 safety and efficacy 86–87, 89 social marketing 88, 88 types 86 see also individual virus infections vaccinia generalized, after vaccination 634 host, distribution 626 post-vaccinial encephalitis 634 vaccinia immune globulin (VIG) 635 vaccinia virus modified vaccinia ankara (MVA) strain 634–635 persistence in environment 49 smallpox vaccination 634 vaccinology 81–93 adverse events 89 burden of disease and reproductive rates 82, 83 disease incidence surveillance 89 future vaccine developments 90 historical aspects 81–82 immune system and artificial immunity 83–85 planning/implementation of programmes 89 principles/practice 82 protective antigen discovery 85–86 protective antigen presentation 86 publicized falsehood rectification 89–90 research and development 86–87, 87 reverse 85 social marketing of vaccines 88, 88 see also vaccination valaciclovir (Valtrex) CMV infection 182, 186 prophylaxis 186, 187–188 herpes zoster 152, 154 HSV infections 109, 113, 114, 117 HSV meningitis 124 structure 109 varicella (chickenpox) 151 valganciclovir (VGCV) CMV infections 181, 189 HSV infections 111 vampire bats, rabies 787, 790, 801 variant Creutzfeldt–Jakob disease (vCJD) 72, 944, 947, 950, 954–956 aetiology and epidemiology 948–949 age of onset 955 BSE association 954 characteristics/diagnosis 950 clinical onset and features 954–955 epidemic 948 first cases 954 incubation period 949, 955, 957 kuru relationship 956 lymphoreticular infection 955–956 molecular diagnosis 959, 960 neuroinvasion 956 neuropathology 955, 956 pathogenesis 960–961 PRNP 129MM and susceptibility 948, 949, 956 PRNP 129VM 956 prognosis and treatment 961 ‘pulvinar sign’ 955 secondary (iatrogenic) 956–957 sporadic CJD vs 956, 957 tonsillar biopsy 955–956, 956, 960–961 transmission 948–949, 960 varicella (chickenpox) 133 children 142, 144 treatment 151–152 clinical features 143–146 complications 144–146 congenital syndrome 145, 145, 152 diagnosis see varicella zoster virus (VZV), detection/diagnosis encephalitis 144–145 epidemiology 48, 142–143 haemorrhagic 144 immunocompromised patients 144, 152 incubation period 52, 143 infants 142 neonates 145–146 pathogenesis of infection 139–141, 140 Subject Index pneumonia associated 144, 144 pneumonitis 152, 154 pregnancy 141, 145–146, 155 prevention 153–156 rash 143–144, 146 recovery and immunity after 141 re-infection 138, 141 required vaccination coverage 82, 82 secondary cases, treatment 151–152 significant exposure (definition) 152 skin lesions 140, 141, 143–144 crusting 140, 144 treatment 151–152 tropical countries and 142 see also varicella zoster virus (VZV) varicella zoster immune globulin (VZIG) 49, 154 dosages 155 efficacy and limitations 154–155 neonatal infections and children 146 pregnancy 155 recommendations/indications 154, 154 varicella zoster virus (VZV) 139 3B3 epitope 149 monoclonal antibodies 138, 148 antibodies to 138–139, 148, 149–150 age prevalence 142, 143 IgG 138, 139, 146 IgM 138, 139, 151 maternal 146 neutralizing 151 antigens 137–138 detection 4, 149–150, 150 HSV cross-reactivity 150 antiviral drug resistance 153 assembly and release (exocytosis) 136 attachment and infection process 136 breakthrough infection 49, 53 capsids 136 cytology 148 cytopathic effect 137, 137, 149 detection/diagnosis 148–151 complement fixation test 150 direct techniques 148 DNA detection 148–149 electron microscopy 148 enzyme immunoassay 150–151 immunofluorescence 148, 150 isolation of VZV 149 PCR 139, 148–149 serology 149–151 gene expression (IE, E and L) 136 genes and proteins 135, 135–136, 141–142 genome (dsDNA) 133–136, 137, 143 HSV homology 134–136 open reading frames 135, 136 organization/sequence 133–134, 134 single nucleotide polymorphisms 137–138 glycoproteins 136, 149 gE 136 HSV cross-reactivity 138, 150 growth in cell culture 137 HCWs and 48–53 HIV co-infection 914 immune response to infection 138–139 cell-mediated 138–139, 142 humoral see varicella zoster virus (VZV), antibodies to immunity in HCWs 48 infection process 140 infections see herpes zoster; varicella (chickenpox) latent infection 133, 141–142, 146 molecular epidemiology 143 MSP-VZV 138 multinucleated cells and inclusions 137, 138, 140, 141, 144, 148, 149 nosocomial infections 48–53 costs 48 management 49 Oka strain 53, 138, 155 genotyping 143 wild-type genome sequence comparison 155 passive immunization 154–155 pathogenesis of infection 139–141, 140 pathogenicity for animals 139 physical characteristics 50 post-exposure prophylaxis 156 prevention of infections 153–156 reactivation 133, 141, 142, 146 in pregnancy 53 synchronous with HSV 107 see also herpes zoster receptors 136 recombinant genotypes 137–138, 143 re-infection with 138, 141 replication 136 rolling circle mechanism 136 shedding 149 strain variation 137–138 structure/morphology 133–136, 134 T-cell response 138–139, 142 tegument proteins 136 TK mutants 153 transmission 52, 139–140, 142 airborne 49, 139 rates to HCWs 48–49 treatment of infections see herpes zoster; varicella (chickenpox) vaccination 49, 155–156 HCWs 49, 51, 53 live attenuated vaccine 49, 53 post-exposure 51 pre-exposure 51, 53 rash post-vaccine 49 reduced nosocomial infections 48 required vaccination coverage 82, 82 vaccines 133, 155–156 efficacy, benefits 155–156 Oka 152, 155, 156 viral load 149 Varicellovirus 95, 96 variola major 626, 628 variola minor 626, 628 variola sine eruptione 629 variolation 81, 90 variola virus 625 antigens 629 host range 627 1013 phenotypic diagnosis 632–633 transmission/infectivity 627–628 see also smallpox vascular endothelial growth factor (VEGF) KSHV infection 252, 263 rhinovirus infection 495 vectors, viruses as adenoviruses 482 measles virus 535 retroviruses 869, 872–873 vectors of viruses, increased contact, emerging infections 74–77 Venezuela haemorrhagic fever 750–751 Venezuelan equine encephalitis virus (VEEV) 643, 644, 646, 659–661 clinical disease 660–661 IgG and IgM 661 origins and distribution 659–660, 660 pathogenesis, diagnosis and control 661 vesicular stomatitis virus, recombinant 770 Vesiculovirus 778 VIDISCA (virus discovery based on cDNA-AFLP) 523 viral interference 414 viral quasispecies 18, 523 viral shedding, qualitative detection of virus 16 viramidine, hepatitis C 315 virologists, communication with physicians 22 viroplasms, rotaviruses 339 ‘virtual phenotyping’ 20 virus amplification, in hospitals 43 viruses persistence in environment 49 physical characteristics 50–51 virus isolation 2–3, VITROS ECi assay, HIV 908 VLA-2, echovirus receptor 605 VX-950, hepatitis C treatment 316 W Wanowrie virus 703, 726 Warthin–Finkeldy cells 543 warts genital 814, 816, 817 laryngeal 813, 815 plantar 813, 817 Wesselsbron virus 673, 679 West Caucasian bat virus 779 Western blotting HIV infection 906–907 HTLVs 879, 880 western equine encephalitis virus (WEEV) 643, 644, 658–659 clinical disease 658 diagnosis 659 epidemiology and host range 658, 659 prevention and control 659 western tick-borne encephalitis virus (W-TBEV) 692, 693 West Nile fever clinical features 690 control 690 diagnosis and antibodies 688, 690 1014 West Nile fever (contd.) epidemics and outbreaks 689–690 epidemiology 689–690 meningoencephalitis 75 neuro-invasive disease 688, 690 rubella differential diagnosis 567 West Nile virus (WNV) 75, 669, 673, 688–690 characteristics and host range 688–689 isolation 690 lineages (I-IV) 688 NY99 prototype 688 transmission cycle 689 vectors 688, 689 Whataroa virus (WHAV) 644 wheezing, recurrent, RSV infection 449–450, 454 Whitewater Arroyo virus 734, 738, 751 detection 741 infections 751 whole-genome sequencing, influenza virus 395 whooping cough, vaccination coverage reduction 90 winter vomiting disease 54 woodchuck hepatitis virus (WHV) 284 World Health Organization (WHO) detection/response on infections 23 poliomyelitis eradication programme 618 rabies vaccine recommendations 800 rubella vaccination recommendations 585, 585–586, 586 SARS prevention recommendations 62 WU virus 74 Wyeomyia virus 702, 707 X xenotropic MuLV-related virus (XMRV) 872 xenotropic murine leukaemia related virus (XMRV) 77 X-linked lymphoproliferative syndrome (X-LPS) 216 Subject Index vector 674 see also flaviviruses Y yattapox virus, host, distribution 626 yeast prions 944 yellow fever 672, 674–678 abortive infection 676 age and gender affecting 677 clinical features 676–677 control 677–678 diagnosis 677 differential diagnosis 676 ‘enzootic forest cycle’ 674 epidemics 674 epidemiology 672, 674–676 Africa 674, 675 Americas 674, 675, 677 haemorrhagic diathesis 676 history 672 incubation period 676 ‘jungle yellow fever cycle’ 674, 676 mortality 676 surveillance for 677 transmission cycles 674, 676 universal/mass immunization 678 ‘urban yellow fever cycle’ 676, 677 vaccine 677–678 contraindications 678 French neurotropic 678 pregnancy 678 production volume 678 side effects 678 viraemia 676 yellow fever virus 672, 674–678 17D vaccine strain 672, 678 Asibi strain 672 detection 677 distribution and vector 673 genotypes 676 isolation/cell lines 677 prM and E proteins 676 transmission 672 Z zalcitabine HAM treatment 890 HIV infection 916 zanamivir HPIV3 infection 413 HPIV infection 429 influenza 60, 398 structure 397 zidovudine adult T-cell leukaemia treatment 890 HAM treatment 890 HIV infection 916, 923 vertical transmission prevention 930 prophylactic 930, 931 resistance 923, 924, 930 Zika fever 684 Zika virus 673, 684 zinc preparations, rhinovirus infections 500 Zinga virus 713 zoonotic infections influenza see influenza A virus; influenza virus retroviruses 869 see also individual animals/vectors zoster see herpes zoster zoster-associated pain (ZAP) 147 treatment 152, 153 zosteriform herpes simplex (cutaneous HSV) 116 zoster immunoglobulin (ZIG) 154 zoster sine herpete 146 Zovirax see aciclovir ... cells virus 1E 1g2B 1g* 1E1g 1E* 1E1g 1g 1E1g2c 1E 1E 1E1g 1E 1C1E 1E 1C 1E 1E 1E 1D 2B 1D* 1D1g 1g 1g* 1B1g 1C 1D 2B 1E1F2B 1B*1C 1E 1C 1C 1C 1a 1a 1D 1E 1C 1C1E 1E2B Figure 23 .2 Global distribution... Virology, 22 7, 314 22 Schneider-Schaulies, S and Dittmer, U (20 06) Silencing T cells or T cell silencing: concepts in virus-induced immunosuppression The Journal of General Virology, 87, 1 423 –38... Organization, 20 06, 20 07) (Figure 23 .2) Genetic analysis of RVs has been used to support rubella control and elimination activities (Icenogle et al., 20 06) The most commonly used vaccine strain of RV, RA27/3,