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The multigenic nature of RNA virus adaptation to plants
OPINION
The multigenic nature of RNA virus adaptation to plants Walter De Jong, Kazuyuki Mise and Paul Ahlquist ost plant viruses can infect many different plant .species, but no virus can infect all plants. The first observation implies that, as a group, viruses have evolved to- thrive in multiple, distinct types of intracellular environments. The second observation, however, shows that there are limits to the adaptation of individual viruses. To understand how individual viruses are successfully adapted to different hosts, it has been productive to analyse cases where an apparently competent virus cannot infect a particular host. In this article, we review recent molecular genetic studies showing that the host range of positivestrand RNA viruses, which make up the majority of known plant viruses, can be influenced by small changes in one or a few viral genes. So far, most such studies have tried to find the specific difference or differences between two closely related viruses or strains of the same virus that allow one virus to infect a particular host while the other related virus cannot. Since these studies are only designed to identify divergent features, each such analysis may only reveal one or a subset of the viral features that directly or indirectly affect interactions with the host. Differences in host range have been shown to result from differences in genes for RNA replication, cell-to-cell movement and capsid proteins, as well as in noncoding regions. It seems that most or all plant RNA virus gene products, and at least some viral noncoding regions, may need to be specifically adapted to the host for full systemic infection. In some cases, accommodation to the host appears to be required for viral gene products to fulfil their primary functions in viral multiplication, while in other cases, adaptation seems to be required to avoid elicit-
Molecular genetic studies of RNA virus host range suggest that successful systemic infection requires many or all viral genes to have some degree of specific adaptation to the host. In some cases, accommodation to the host appears to be required for viral gene products to fulfil their primary functions in viral multiplication, while in other cases, adaptation seems to be required to avoid eliciting host defenses.
M
W. De Jong and P. Ahlquist are in the Institute for Molecular Virology and Dept of Plant Pathology, University of
Wisconsin-Madison, 1525 Linden Drive, Madison, WI 53 706, USA; K. Mise is in the Laboratory of Plant Pathology, Faculty of Agriculture, Kyoto University, Kyoto 606-01, Japan.
ing host defenses. We will describe only a few of many examples; for additional information on virushost interactions, see the excellent reviews in Refs 1,2. Adaptation of RNA replication genes to the host The replication of bacteriophage QP depends on recruiting multiple host proteins (and a single viral protein) into an RNA-dependent RNA polymerase (RdRp) complex. The copurification of host proteins with viral RdRp preparations suggests that this may also apply to eukaryotic plant RNA viruses, and other studies support this view3x4. One of the host proteins that copurifies with brome mosaic virus (BMV) RdRp reacts with antisera prepared against eukaryotic translation initiation factor 3 and, when added exogenously, stimulates BMV RdRp activity in vitro4. It is conceivable that intra- or interspecific differences in host factors required for viral RNA replication could prevent or reduce the rate of RNA repli0
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sciencr
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cation, if some host-factor isoforms cannot interact optimally with viral Significant natural components. variation may be rare, however, as BMV can replicate in yeast, a nonplant hosts. There is also evidence that tobacco mosaic virus (TMV) can replicate in yeas@. Nevertheless, tomatoes homozygous for the Tm-2 resistance gene strongly inhibit TMV RNA accumulation, Tm-1 resisteven in protoplasts. ance is overcome by any of several sets of a small number of amino acid changes that lower the net charge of the TMV 126 kDa replication protein’. In most cases where there is a requirement for RNA replication genes to be adapted, the requirement does not completely block RNA replication. For example, BMV systemically infects barley, while cowpea chlorotic mottle virus (CCMV) infects cowpea. Reciprocal hybrids constructed between tripartite BMV and CCMV by exchanging both RNA1 and RNA2 together (encoding the helicase-like la and polymerase-like 2a replication proteins respectively) multiply in isolated protoplasts from a variety of plants. However, the hybrids cannot infect either barley or cowpea systemically, showing that RNA1 and/or RNA2 influence bromoviral host range*. In tobacco, the dominant N gene mediates hypersensitive resistance (HR) against almost all tobamoviruses. Mutagenesis of a tobamovirus that evades N-mediated HR in tobacco has shown that a single change in the 126kDa replication gene abolishes the ability of this strain to avoid HR (Ref. 9). Where RNA replication is not completely blocked, differences in the rates or final levels of RNA accumulation may influence host range. In some or all of these cases, adaptation of replication genes to specific hosts may
OPINION
reflect additional activities of these genes in roles not directly related to RNA replication. Adaptation of movement protein genes Cell-to-cell movement proteins are nonstructural proteins required by plant viruses to move between cellslo. They are thought to act, at least in part, by modifying the narrow intercellular channels (plasmodesmata) that connect most plant cells. Studies with strains of TMV that have overcome the Tm-2 and Tm-22 resistance alleles in tomato provide strong evidence that the function of TMV movement proteins depends on proper host interaction. Tm-2 and Tm-22 resistance alleles block the spread of infection from initially infected cells to neighboring cells without affecting RNA replication”. Changes in TMV sufficient to overcome Tm-2 and Tm-22 resistance map to the 30 kDa movement protein12J3. Like the changes in the 126kDa protein that break Tm-I resistance, the changes that overcome Tm-2 resistance and those that overcome Tm-22 resistance alter the net charge of the 30 kDa protein12J3. As well as bromoviral replication genes, bromoviral movement protein genes are also involved in host specificity. A hybrid bromovirus with the 3a movement protein gene of CCMV replaced with that of BMV can spread systemically in Nicotiana benthamiana, a common host for the parental viruses, but cannot infect cowpea systemically14. Several pseudorevertants of this hybrid were obtained that infect cowpea systemically, suggesting that only a few changes are required to adapt the BMV 3a gene to cowpeai4. Although the wild-type BMV gene cannot functionally replace the 3a movement protein gene of icosahedral CCMV, this gene can be functionally replaced by the 30 kDa movement protein gene of the rod-shaped sunn-hemp mosaic virus15. Adaptation of coat protein genes For animal viruses, capsid proteins are often important determinants of host and tissue specificity, as interactions between the viral cap-
sid and defined plasma membrane receptors are often crucial for the entry of viruses into particular host cells. There is, however, no evidence that plant viruses enter plant cells by receptor-mediated endocytosis. Thus, the observation that plant virus coat protein genes can influence host range cannot be linked to variation in host cell-surface receptors that prevents initial viral entry. For many (but not all) plant viruses, the coat protein is required for long-distance vascular transport; a recent study provides evidence that the role of the coat protein in long-distance transport can be host specifi@. A TMV hybrid with an Odontoglossum ringspot virus capsid protein gene spreads within inoculated leaves of tobacco at rates similar to those of wild-type TMV but, unlike TMV, it cannot move efficiently from inoculated to uninoculated leaves. In several cases, the coat protein has been identified as the entity ‘recognized’ by resistance genes. In potato, both the Rx and Nx genes confer resistance to some strains of potato virus X (PVX) and changes in the PVX coat protein are sufficient to overcome both resistance genes”. In Nicotiana species, the N’ gene confers HR to many isolates of TMV. TMV coat protein is sufficient to trigger N’-mediated resistance as N’ plants or calli, transformed to express the coat protein, undergo HR (Refs l&19). Adaptation of noncoding regions Noncoding regions can also influence viral interactions with their hosts. The type strain of barley stripe mosaic virus has a small open reading frame (ORF) that other strains lack, just upstream of the p RNA-polymerase-like gene. In vitro, this small ORF reduces the level of p expression. The presence of this small ORF correlates with an inability to infect N. benthamiunu systemically20, which suggests that the level of expression of p is a determinant of host specificity. For CCMV, the noncoding, intercistronic region of RNA3 influences pathogenesis: deleting certain bits of this region dramatically intensifies symptoms2’.
For tobacco vein mottling virus, alterations in the 3’ noncoding region can also affect the intensity of symptoms22. Relevant host components The studies reviewed here suggest that many or all viral gene products and noncoding regions need to be adapted to the host simultaneously for successful infection. This in turn implies that infection is a complex interplay between many viral and plant factors. At the moment, there are few clues about the identity of the host factors to which viruses must be properly adapted. There is a variety of evidence that interactions with host proteins are involved in processes like RNA replication and cell-to-cell spread; indeed, specific direct interaction with host proteins is probably essential for many viral processes. Nevertheless, indirect interactions and interactions with nonproteinaceous factors may also influence host range. Sindbis virus cannot multiply efficiently in methionine-deprived mosquito cells, possibly because lowered S-adenosyl methionine pools interfere with methylation of the 5’ caps on viral RNAs. Point changes in the Sindbis methyltransferase protein that increase affinity for S-adenosyl methionine and increase m7G methyltransferase activity allow Sindbis to replicate when deprived of methionine23. Thus, host-specific variation at the level of S-adenosyl methionine or other low-molecularmass substrates or cofactors could limit host range. For many positive-strand RNA viruses of animals and plants, RNA replication complexes are associated with membranes. Certain lipids are essential for complete replication of flock house virus RNA in an in vitro system14, and poliovirus RNA replication in vivo is completely blocked by brefeldin A, a drug that perturbs the structure and function of the endoplasmic reticulum and Golgi membrane complexes25. Accordingly, host-specific variation in lipid synthesis and membrane traffic may also influence viral host range. The idea that many or all viral genes and infection processes may
BOOK
need to be accommodated to some degree to the host derives from years of effort by many workers, analysing many different host-virus systems. The identification of host components with which viruses interact differentially should significantly increase understanding of host specificity and the mechanisms of virus infection, and may open new possibilities for viral control. Acknowledgements
Researchon thesetopics in our laboratory was conducted under grants DMB9004385 from the National ScienceFoundation and GM35072 from the National Institutes of Health. References 1 Dawson, W.O. and Hilf, M.E. (1992) Annu. Rev. Plant Physiol. 43, 527-555 2 Zaitlin, M. and Hull, R. (1987) Annu. Rev. Plant Physiol. 38,291-315 3 Hayes, R.J. and Buck, K.W. (1990) Cell
Herpesviruses in a postGenome-Project world The Human Herpesviruses edited by B. Roizman, R.J. Whitley and C. Lopez Raven Press, 1993. $113.50 hbk (xi + 433 pages) ISBN 0 7817 0024 8 The herpesviruses are a numerous family defined by their complex virion morphology and large DNA genomes. There are seven known to have humans as their natural host. These human herpesviruses are a diverse lot, at every level: genome size, gene complement, natural history and disease. They include representatives from all three major lineages of the family: from the a-herpesvirinae, herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV); from the j3-herpesvirinae, human cytomegalovirus (HCMV) and (still to be blessed by taxonomic writ) the recently discovered human herpesviruses 6 and 7; and from the y-herpesvirinae, Epstein-Barr virus (EBV). Understandably, they also include the best characterized members of the herpesvirus family. Most humans become exposed
REVIEWS
63,363-368 4 Quadt, R. et al. (1993) Proc. Nat1Acad. Sci. USA 90,1498-1502 5 Janda, M. and Ahlquist, P. (1993) Cell 72,961-970 6 Coutts, R.H.A., Cocking, E.C. and Kassanis, B. (1972) Nature 240,466-467 7 Meshi, T. et al. (1988) EMBO J. 7,1575-1581 8 Allison, R.F., Janda, M. and Ahlquist, P. (1988) 1. Viral. 62,3581-3588 9 Padgett, H.S. and Beachy, R.N. (1993) Plant Cell 5,577-586 10 Deom, C.M., Lapidot, M. and Beachy, R.N. (1992) Cell 69,221-224 11 Nishiguchi, M. and Motoyoshi, F. (1987) in Plant Resistance to Viruses (Evered, S. and Harnett, S., eds), pp. 38-46, John Wiley & Sons 12 Meshi, T. et al. (1989) Plant Cell 1,515-522 13 Weber, H., Schultze, S. and Pfitzner, A.J.P. (1993)]. Viral. 67,6432-6438 14 Mise, K. et al. (1993) J. Virol. 67, 2815-2823 15 De Jong, W. and Ahlquist, P. (1992)
Proc. Nat1 Acad. Sci. USA89,68084812 16 Hilf, M.E. and Dawson, W.O. (1993) Virology 193,106-114 17 Kavanagh, T. et al. (1992) Virology 189, 609-617 18 Culver, J.N. and Dawson, W.O. (1991) Mol. Plant-Microbe Interact. 4, 458-463 19 Pfitzner, U.M. and Pfitzner, A.J.P. (1992) Mol. Plant-Microbe Interact. 5, 318-321 20 Petty, I.T.D., Edwards, M.C. and Jackson, A.O. (1990) Proc. Nat1 Acad. Sci. USA 87,8894-8897 21 Pacha, R.F. and Ahlquist, P. (1992) Virology 187,298-307 22 Rodriguez-Cerezo, E., Gamble Klein, P. and Shaw, J.G. (1991) Proc. Nat1Acad. Sci. USA 88,9863-9867 23 Mi, S. and Stellar, V. (1990) Virology 178,429-434 24 Wu, S-X., Ahlquist, P. and Kaesberg, P. (1992) Proc. Nat1Acad. Sci. USA 89,11136-11140 25 Maynell, L.A., Kirkegaard, K. and Klymkowsky, M.W. (1992) J. Virol. 66,1985-1994
to most of these viruses at an early age, and the viruses are in general highly prevalent in populations. The primarily genital HSV-2 is an exception, but in societies particularly devoted to liberty and the pursuit of happiness, its incidence too is becoming very substantial. Control measures are improving but incomplete: nucleoside analogues active against herpesviruses represent the great success story of antiviral chemistry, but only one vaccine (against VZV) is used significantly. Members of the herpesvirus family have two general features of their behaviour: on primary infection they enter a state of lifelong latent infection with occasional reactivation, and usually they do not cause serious disease. When the accommodation between organism and virus is lost, however, the consequences can be serious indeed: HSV can cause ocular disease and also devastating encephalitis; shingles is the re-emergence of VZV previously experienced as chickenpox; HCMV is now the major viral cause of congenital abnormality in countries where rubella virus is controlled; EBV is implicated in several cancers; all cause severe disease in the immunocompromised.
In the 198Os, the complete genomic sequences of EBV, VZV, HSV-1 and HCMV were analysed in laboratories in the UK. In their day, these were very large-scale sequencing projects, and with 229354 bp HCMV DNA is still one of the longest sequences that have been determined. The gene complements that were revealed in detail brought research on herpesviruses into sharp focus: comparisons showed that these viruses did indeed share their evolutionary origins, having a common core set of some 40 genes. There are also familyand species-specific sets another 30 for the of genes: a-herpesviruses, perhaps another 160 for HCMV. Many of the genes discovered had not been previously characterized to a significant extent, even in the much-studied HSV-1, and so analysis of the genes and their products has flowered in this ‘post-Genome-Project’ world, components of subsystems have been listed and their biochemical logic traced. About half of the genes of HSV-1 have been found to be dispensable for growth in tissue mutants, reculture in singie emphasizing that use of tissue
The multigenic nature of RNA virus adaptation to plants Walter De Jong, Kazuyuki Mise and Paul Ahlquist ost plant viruses can infect many different plant .species, but no virus can infect all plants. The first observation implies that, as a group, viruses have evolved to- thrive in multiple, distinct types of intracellular environments. The second observation, however, shows that there are limits to the adaptation of individual viruses. To understand how individual viruses are successfully adapted to different hosts, it has been productive to analyse cases where an apparently competent virus cannot infect a particular host. In this article, we review recent molecular genetic studies showing that the host range of positivestrand RNA viruses, which make up the majority of known plant viruses, can be influenced by small changes in one or a few viral genes. So far, most such studies have tried to find the specific difference or differences between two closely related viruses or strains of the same virus that allow one virus to infect a particular host while the other related virus cannot. Since these studies are only designed to identify divergent features, each such analysis may only reveal one or a subset of the viral features that directly or indirectly affect interactions with the host. Differences in host range have been shown to result from differences in genes for RNA replication, cell-to-cell movement and capsid proteins, as well as in noncoding regions. It seems that most or all plant RNA virus gene products, and at least some viral noncoding regions, may need to be specifically adapted to the host for full systemic infection. In some cases, accommodation to the host appears to be required for viral gene products to fulfil their primary functions in viral multiplication, while in other cases, adaptation seems to be required to avoid elicit-
Molecular genetic studies of RNA virus host range suggest that successful systemic infection requires many or all viral genes to have some degree of specific adaptation to the host. In some cases, accommodation to the host appears to be required for viral gene products to fulfil their primary functions in viral multiplication, while in other cases, adaptation seems to be required to avoid eliciting host defenses.
M
W. De Jong and P. Ahlquist are in the Institute for Molecular Virology and Dept of Plant Pathology, University of
Wisconsin-Madison, 1525 Linden Drive, Madison, WI 53 706, USA; K. Mise is in the Laboratory of Plant Pathology, Faculty of Agriculture, Kyoto University, Kyoto 606-01, Japan.
ing host defenses. We will describe only a few of many examples; for additional information on virushost interactions, see the excellent reviews in Refs 1,2. Adaptation of RNA replication genes to the host The replication of bacteriophage QP depends on recruiting multiple host proteins (and a single viral protein) into an RNA-dependent RNA polymerase (RdRp) complex. The copurification of host proteins with viral RdRp preparations suggests that this may also apply to eukaryotic plant RNA viruses, and other studies support this view3x4. One of the host proteins that copurifies with brome mosaic virus (BMV) RdRp reacts with antisera prepared against eukaryotic translation initiation factor 3 and, when added exogenously, stimulates BMV RdRp activity in vitro4. It is conceivable that intra- or interspecific differences in host factors required for viral RNA replication could prevent or reduce the rate of RNA repli0
IV94
Elsevw
sciencr
Id
OY66
842X/Y4/$07.00
cation, if some host-factor isoforms cannot interact optimally with viral Significant natural components. variation may be rare, however, as BMV can replicate in yeast, a nonplant hosts. There is also evidence that tobacco mosaic virus (TMV) can replicate in yeas@. Nevertheless, tomatoes homozygous for the Tm-2 resistance gene strongly inhibit TMV RNA accumulation, Tm-1 resisteven in protoplasts. ance is overcome by any of several sets of a small number of amino acid changes that lower the net charge of the TMV 126 kDa replication protein’. In most cases where there is a requirement for RNA replication genes to be adapted, the requirement does not completely block RNA replication. For example, BMV systemically infects barley, while cowpea chlorotic mottle virus (CCMV) infects cowpea. Reciprocal hybrids constructed between tripartite BMV and CCMV by exchanging both RNA1 and RNA2 together (encoding the helicase-like la and polymerase-like 2a replication proteins respectively) multiply in isolated protoplasts from a variety of plants. However, the hybrids cannot infect either barley or cowpea systemically, showing that RNA1 and/or RNA2 influence bromoviral host range*. In tobacco, the dominant N gene mediates hypersensitive resistance (HR) against almost all tobamoviruses. Mutagenesis of a tobamovirus that evades N-mediated HR in tobacco has shown that a single change in the 126kDa replication gene abolishes the ability of this strain to avoid HR (Ref. 9). Where RNA replication is not completely blocked, differences in the rates or final levels of RNA accumulation may influence host range. In some or all of these cases, adaptation of replication genes to specific hosts may
OPINION
reflect additional activities of these genes in roles not directly related to RNA replication. Adaptation of movement protein genes Cell-to-cell movement proteins are nonstructural proteins required by plant viruses to move between cellslo. They are thought to act, at least in part, by modifying the narrow intercellular channels (plasmodesmata) that connect most plant cells. Studies with strains of TMV that have overcome the Tm-2 and Tm-22 resistance alleles in tomato provide strong evidence that the function of TMV movement proteins depends on proper host interaction. Tm-2 and Tm-22 resistance alleles block the spread of infection from initially infected cells to neighboring cells without affecting RNA replication”. Changes in TMV sufficient to overcome Tm-2 and Tm-22 resistance map to the 30 kDa movement protein12J3. Like the changes in the 126kDa protein that break Tm-I resistance, the changes that overcome Tm-2 resistance and those that overcome Tm-22 resistance alter the net charge of the 30 kDa protein12J3. As well as bromoviral replication genes, bromoviral movement protein genes are also involved in host specificity. A hybrid bromovirus with the 3a movement protein gene of CCMV replaced with that of BMV can spread systemically in Nicotiana benthamiana, a common host for the parental viruses, but cannot infect cowpea systemically14. Several pseudorevertants of this hybrid were obtained that infect cowpea systemically, suggesting that only a few changes are required to adapt the BMV 3a gene to cowpeai4. Although the wild-type BMV gene cannot functionally replace the 3a movement protein gene of icosahedral CCMV, this gene can be functionally replaced by the 30 kDa movement protein gene of the rod-shaped sunn-hemp mosaic virus15. Adaptation of coat protein genes For animal viruses, capsid proteins are often important determinants of host and tissue specificity, as interactions between the viral cap-
sid and defined plasma membrane receptors are often crucial for the entry of viruses into particular host cells. There is, however, no evidence that plant viruses enter plant cells by receptor-mediated endocytosis. Thus, the observation that plant virus coat protein genes can influence host range cannot be linked to variation in host cell-surface receptors that prevents initial viral entry. For many (but not all) plant viruses, the coat protein is required for long-distance vascular transport; a recent study provides evidence that the role of the coat protein in long-distance transport can be host specifi@. A TMV hybrid with an Odontoglossum ringspot virus capsid protein gene spreads within inoculated leaves of tobacco at rates similar to those of wild-type TMV but, unlike TMV, it cannot move efficiently from inoculated to uninoculated leaves. In several cases, the coat protein has been identified as the entity ‘recognized’ by resistance genes. In potato, both the Rx and Nx genes confer resistance to some strains of potato virus X (PVX) and changes in the PVX coat protein are sufficient to overcome both resistance genes”. In Nicotiana species, the N’ gene confers HR to many isolates of TMV. TMV coat protein is sufficient to trigger N’-mediated resistance as N’ plants or calli, transformed to express the coat protein, undergo HR (Refs l&19). Adaptation of noncoding regions Noncoding regions can also influence viral interactions with their hosts. The type strain of barley stripe mosaic virus has a small open reading frame (ORF) that other strains lack, just upstream of the p RNA-polymerase-like gene. In vitro, this small ORF reduces the level of p expression. The presence of this small ORF correlates with an inability to infect N. benthamiunu systemically20, which suggests that the level of expression of p is a determinant of host specificity. For CCMV, the noncoding, intercistronic region of RNA3 influences pathogenesis: deleting certain bits of this region dramatically intensifies symptoms2’.
For tobacco vein mottling virus, alterations in the 3’ noncoding region can also affect the intensity of symptoms22. Relevant host components The studies reviewed here suggest that many or all viral gene products and noncoding regions need to be adapted to the host simultaneously for successful infection. This in turn implies that infection is a complex interplay between many viral and plant factors. At the moment, there are few clues about the identity of the host factors to which viruses must be properly adapted. There is a variety of evidence that interactions with host proteins are involved in processes like RNA replication and cell-to-cell spread; indeed, specific direct interaction with host proteins is probably essential for many viral processes. Nevertheless, indirect interactions and interactions with nonproteinaceous factors may also influence host range. Sindbis virus cannot multiply efficiently in methionine-deprived mosquito cells, possibly because lowered S-adenosyl methionine pools interfere with methylation of the 5’ caps on viral RNAs. Point changes in the Sindbis methyltransferase protein that increase affinity for S-adenosyl methionine and increase m7G methyltransferase activity allow Sindbis to replicate when deprived of methionine23. Thus, host-specific variation at the level of S-adenosyl methionine or other low-molecularmass substrates or cofactors could limit host range. For many positive-strand RNA viruses of animals and plants, RNA replication complexes are associated with membranes. Certain lipids are essential for complete replication of flock house virus RNA in an in vitro system14, and poliovirus RNA replication in vivo is completely blocked by brefeldin A, a drug that perturbs the structure and function of the endoplasmic reticulum and Golgi membrane complexes25. Accordingly, host-specific variation in lipid synthesis and membrane traffic may also influence viral host range. The idea that many or all viral genes and infection processes may
BOOK
need to be accommodated to some degree to the host derives from years of effort by many workers, analysing many different host-virus systems. The identification of host components with which viruses interact differentially should significantly increase understanding of host specificity and the mechanisms of virus infection, and may open new possibilities for viral control. Acknowledgements
Researchon thesetopics in our laboratory was conducted under grants DMB9004385 from the National ScienceFoundation and GM35072 from the National Institutes of Health. References 1 Dawson, W.O. and Hilf, M.E. (1992) Annu. Rev. Plant Physiol. 43, 527-555 2 Zaitlin, M. and Hull, R. (1987) Annu. Rev. Plant Physiol. 38,291-315 3 Hayes, R.J. and Buck, K.W. (1990) Cell
Herpesviruses in a postGenome-Project world The Human Herpesviruses edited by B. Roizman, R.J. Whitley and C. Lopez Raven Press, 1993. $113.50 hbk (xi + 433 pages) ISBN 0 7817 0024 8 The herpesviruses are a numerous family defined by their complex virion morphology and large DNA genomes. There are seven known to have humans as their natural host. These human herpesviruses are a diverse lot, at every level: genome size, gene complement, natural history and disease. They include representatives from all three major lineages of the family: from the a-herpesvirinae, herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV); from the j3-herpesvirinae, human cytomegalovirus (HCMV) and (still to be blessed by taxonomic writ) the recently discovered human herpesviruses 6 and 7; and from the y-herpesvirinae, Epstein-Barr virus (EBV). Understandably, they also include the best characterized members of the herpesvirus family. Most humans become exposed
REVIEWS
63,363-368 4 Quadt, R. et al. (1993) Proc. Nat1Acad. Sci. USA 90,1498-1502 5 Janda, M. and Ahlquist, P. (1993) Cell 72,961-970 6 Coutts, R.H.A., Cocking, E.C. and Kassanis, B. (1972) Nature 240,466-467 7 Meshi, T. et al. (1988) EMBO J. 7,1575-1581 8 Allison, R.F., Janda, M. and Ahlquist, P. (1988) 1. Viral. 62,3581-3588 9 Padgett, H.S. and Beachy, R.N. (1993) Plant Cell 5,577-586 10 Deom, C.M., Lapidot, M. and Beachy, R.N. (1992) Cell 69,221-224 11 Nishiguchi, M. and Motoyoshi, F. (1987) in Plant Resistance to Viruses (Evered, S. and Harnett, S., eds), pp. 38-46, John Wiley & Sons 12 Meshi, T. et al. (1989) Plant Cell 1,515-522 13 Weber, H., Schultze, S. and Pfitzner, A.J.P. (1993)]. Viral. 67,6432-6438 14 Mise, K. et al. (1993) J. Virol. 67, 2815-2823 15 De Jong, W. and Ahlquist, P. (1992)
Proc. Nat1 Acad. Sci. USA89,68084812 16 Hilf, M.E. and Dawson, W.O. (1993) Virology 193,106-114 17 Kavanagh, T. et al. (1992) Virology 189, 609-617 18 Culver, J.N. and Dawson, W.O. (1991) Mol. Plant-Microbe Interact. 4, 458-463 19 Pfitzner, U.M. and Pfitzner, A.J.P. (1992) Mol. Plant-Microbe Interact. 5, 318-321 20 Petty, I.T.D., Edwards, M.C. and Jackson, A.O. (1990) Proc. Nat1 Acad. Sci. USA 87,8894-8897 21 Pacha, R.F. and Ahlquist, P. (1992) Virology 187,298-307 22 Rodriguez-Cerezo, E., Gamble Klein, P. and Shaw, J.G. (1991) Proc. Nat1Acad. Sci. USA 88,9863-9867 23 Mi, S. and Stellar, V. (1990) Virology 178,429-434 24 Wu, S-X., Ahlquist, P. and Kaesberg, P. (1992) Proc. Nat1Acad. Sci. USA 89,11136-11140 25 Maynell, L.A., Kirkegaard, K. and Klymkowsky, M.W. (1992) J. Virol. 66,1985-1994
to most of these viruses at an early age, and the viruses are in general highly prevalent in populations. The primarily genital HSV-2 is an exception, but in societies particularly devoted to liberty and the pursuit of happiness, its incidence too is becoming very substantial. Control measures are improving but incomplete: nucleoside analogues active against herpesviruses represent the great success story of antiviral chemistry, but only one vaccine (against VZV) is used significantly. Members of the herpesvirus family have two general features of their behaviour: on primary infection they enter a state of lifelong latent infection with occasional reactivation, and usually they do not cause serious disease. When the accommodation between organism and virus is lost, however, the consequences can be serious indeed: HSV can cause ocular disease and also devastating encephalitis; shingles is the re-emergence of VZV previously experienced as chickenpox; HCMV is now the major viral cause of congenital abnormality in countries where rubella virus is controlled; EBV is implicated in several cancers; all cause severe disease in the immunocompromised.
In the 198Os, the complete genomic sequences of EBV, VZV, HSV-1 and HCMV were analysed in laboratories in the UK. In their day, these were very large-scale sequencing projects, and with 229354 bp HCMV DNA is still one of the longest sequences that have been determined. The gene complements that were revealed in detail brought research on herpesviruses into sharp focus: comparisons showed that these viruses did indeed share their evolutionary origins, having a common core set of some 40 genes. There are also familyand species-specific sets another 30 for the of genes: a-herpesviruses, perhaps another 160 for HCMV. Many of the genes discovered had not been previously characterized to a significant extent, even in the much-studied HSV-1, and so analysis of the genes and their products has flowered in this ‘post-Genome-Project’ world, components of subsystems have been listed and their biochemical logic traced. About half of the genes of HSV-1 have been found to be dispensable for growth in tissue mutants, reculture in singie emphasizing that use of tissue