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Interactions between viruses, cells and the host immune response that underlie the pathogenesis of viral diseases
433
Host—microbe interactions: viruses Interactions between viruses, cells and the host immune response that underlie the pathogenesis of viral diseases Editorial overview Diane E Griffin Addresses Johns Hopkins University, Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, Maryland 21205, USA e-mail: [email protected] Current Opinion in Microbiology 2001, 4:433–434. 1369-5274/00/$ – see front matter. © 2001 Elsevier Science Ltd. All rights reserved. Abbreviations ASFV African swine fever virus HS heparan sulfate SA sialic acid VZV varicella-zoster virus
Viruses were the first pathogens to have complete sequence information available. At least one representative and, often, many representatives of each virus family have been sequenced. The genomes have revealed and continue to reveal much about the predicted types of viral proteins encoded, about virus evolution, conservation of genetic information, efficient use of small coding capacities, and about the significant consequences of apparently minor coding and noncoding changes for virulence. However, as more and more viruses have been sequenced, it has quickly become apparent that, even for those with the smallest genomes, obtaining the sequence is only a very first step toward understanding virus-induced disease. The ‘postgenomic era’ of virology has provided fascinating glimpses into the complexities of virus–host cell and virus–host interactions. One important lesson that is illustrated by studies of a number of viruses, including rotaviruses, varicella-zoster virus (VZV) and African swine fever virus (ASFV), is that investigation of the functions of many viral proteins cannot rely solely on studies of virus infection of tissue culture cells. Receptors that are used in vitro are often not the ones used in vivo. Genes that encode proteins not essential for replication in cultured cells are often necessary for replication in host tissue, for spread or for causing disease in the host. Some viruses, such as the arthropod-borne viruses illustrated in this Host–microbe interactions: viruses section of Current Opinion in Microbiology by the flaviviruses and ASFV, have more than one host that must be successfully infected. Thus, studies of virus–host interactions have increasingly moved to studies of animal model systems or infections of natural hosts to obtain information relevant to disease pathogenesis.
in which they are propagated. The first step in this process is the binding of the virus to the cell surface, often regarded as the interaction between the virus and its cellular receptor. However, this is often an electrostatic interaction influenced by the presence of negatively charged molecules on the cell surface and clusters of positively charged amino acids on the virion surface. Glycosylation of cell surface proteins and lipids, with the addition of glycosaminoglycans and terminal sialic acid residues, contributes much of the negative charge. Many viruses bind the glycosaminoglycan heparan sulfate (HS), and this molecule has been identified as the ‘receptor’ for viruses with very different in vivo cell and tissue tropisms (e.g. many herpes viruses, Sindbis virus, dengue virus, foot-and-mouth-disease virus, adenoassociated virus, respiratory syncytial virus, papillomavirus and vaccinia virus). It is now clear that for many of these viruses, HS binding represents a tissue culture adaptation with selection for mutations that increase the numbers of positively charged amino acids on the virion surface. These amino acid changes often decrease virulence in vivo. For instance, strains of Sindbis virus that bind HS well replicate optimally in tissue culture, but subcutaneous infection of mice with the same strains leads to lower level viremia and more rapid clearance from the circulation than is observed for strains that do not bind HS and replicate less well in vitro [1]. Thus, a decreased ability to bind HS leads to more efficient viral production in vivo. As Ciarlet and Estes (pp 435–441) point out, a similar situation may exist for sialic acid (SA) binding by rotaviruses. In this case, one of the viral surface proteins (VP8*) binds SA in strains that grow easily in tissue culture, but interaction of a second viral protein (VP5*) with the cell surface is necessary for infection, and interaction with SA is not necessary for rotavirus-induced diarrhea in experimental animals. The need to interact with more than one cell surface molecule, or the use of a co-receptor, is increasingly recognized to be necessary for the entry of many viruses. The presence or absence of a necessary coreceptor can help to explain host range, cell and tissue tropism and varied efficiency of infection. In addition, viruses such as VZV (Arvin, pp 442–449) may require the participation of more than one viral surface protein for efficient attachment and entry. These molecules may also induce cell-signaling events that are necessary for virus infection, as postulated for some rotaviruses.
Virus–receptor interactions and virus entry Strains of viruses that are studied in the laboratory are selected for efficient replication in the tissue culture cells
How viruses traverse the cell membrane to deliver their genomes and initiate infection is an area of active study.
434 Host–microbe interactions: viruses
Enveloped viruses must fuse their lipid membranes with the plasma membrane and this process is best understood for viruses with viral surface proteins that form α-helix coiled coils similar to those formed by cellular fusion proteins. These class I viral fusion proteins are present in orthomyxoviruses, paramyxoviruses, retroviruses and filoviruses. However, not all virus fusion proteins are predicted to form these structures, and Heinz and Allison (pp 450–455) present recent crystallographic studies of the surface fusion glycoproteins of flaviviruses and alphaviruses, both arthropod-borne viruses, that indicate that they represent a new class of viral fusion proteins, class II proteins. These proteins have internal fusion peptides and form trimers without coiled coils and are the first recognized members of this class of proteins.
Virus–host interactions Large DNA viruses such as poxviruses [2], herpesviruses [2,3] (e.g. VZV) and ASFV have a particularly interesting abundance of ‘nonessential’ genes encoding proteins essential for virulence. These proteins may interfere with the immune response by inhibiting major histocompatibility (MHC) antigen expression on infected cells (e.g., the inhibition by VZV proteins of both class I and class II expression), inhibiting cytokine production by infected cells (e.g. cells infected with 5EL or ASFV), or inhibiting cytokine function during the immune response [2,3]. These genes may also determine the fate of the infected cell by inducing or blocking programmed cell death. The genes MGF530 and MGF360 of ASFV are an example of this.
In addition, the outcome of infection often varies with the genetic background of the host, as well as the virus. The ability of the immune system to clear virus from infected cells and tissues is particularly important. ASFV causes persistent nonfatal infection in warthogs and bushpigs, important for the maintenance of the natural cycle, but may cause rapidly fatal disease in domestic swine (Tulman and Rock, pp 456–461). The inability of the host immune system to clear virus can also lead to progressive disease, as illustrated by the human immunodeficiency virus and the hepatitis C virus. Virus persistence in the nervous system can lead to a variety of diseases, as illustrated by Haring and Perlman (pp 462–466) for mouse-hepatitis virusinduced demyelination, and by Carbone et al. (pp 467–475) for Borna-disease-virus-induced neurodegeneration. Diseases may be mediated by the immune response to viral antigens in persistently infected cells or to progressive virusinduced cell loss. Continuing to unravel these complicated virus–host interactions will provide interesting and important insights into the interactive functions of genes from both the virus and the host.
References 1.
Byrnes AP, Griffin DE: Large-plaque mutants of Sindbis virus show reduced binding to heparan sulfate, heightened viremia, and slower clearance from the circulation. J Virol 2000, 74:644-651.
2.
McFadden G, Murphy PM: Host-related immunomodulators encoded by poxviruses and herpesviruses. Curr Opin Microbiol 2000, 3:371-378.
3.
Brander C, Walker BD: Modulation of host immune responses by clinically relevant human DNA and RNA viruses. Curr Opin Microbiol 2000, 3:379-386.
Host—microbe interactions: viruses Interactions between viruses, cells and the host immune response that underlie the pathogenesis of viral diseases Editorial overview Diane E Griffin Addresses Johns Hopkins University, Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, Maryland 21205, USA e-mail: [email protected] Current Opinion in Microbiology 2001, 4:433–434. 1369-5274/00/$ – see front matter. © 2001 Elsevier Science Ltd. All rights reserved. Abbreviations ASFV African swine fever virus HS heparan sulfate SA sialic acid VZV varicella-zoster virus
Viruses were the first pathogens to have complete sequence information available. At least one representative and, often, many representatives of each virus family have been sequenced. The genomes have revealed and continue to reveal much about the predicted types of viral proteins encoded, about virus evolution, conservation of genetic information, efficient use of small coding capacities, and about the significant consequences of apparently minor coding and noncoding changes for virulence. However, as more and more viruses have been sequenced, it has quickly become apparent that, even for those with the smallest genomes, obtaining the sequence is only a very first step toward understanding virus-induced disease. The ‘postgenomic era’ of virology has provided fascinating glimpses into the complexities of virus–host cell and virus–host interactions. One important lesson that is illustrated by studies of a number of viruses, including rotaviruses, varicella-zoster virus (VZV) and African swine fever virus (ASFV), is that investigation of the functions of many viral proteins cannot rely solely on studies of virus infection of tissue culture cells. Receptors that are used in vitro are often not the ones used in vivo. Genes that encode proteins not essential for replication in cultured cells are often necessary for replication in host tissue, for spread or for causing disease in the host. Some viruses, such as the arthropod-borne viruses illustrated in this Host–microbe interactions: viruses section of Current Opinion in Microbiology by the flaviviruses and ASFV, have more than one host that must be successfully infected. Thus, studies of virus–host interactions have increasingly moved to studies of animal model systems or infections of natural hosts to obtain information relevant to disease pathogenesis.
in which they are propagated. The first step in this process is the binding of the virus to the cell surface, often regarded as the interaction between the virus and its cellular receptor. However, this is often an electrostatic interaction influenced by the presence of negatively charged molecules on the cell surface and clusters of positively charged amino acids on the virion surface. Glycosylation of cell surface proteins and lipids, with the addition of glycosaminoglycans and terminal sialic acid residues, contributes much of the negative charge. Many viruses bind the glycosaminoglycan heparan sulfate (HS), and this molecule has been identified as the ‘receptor’ for viruses with very different in vivo cell and tissue tropisms (e.g. many herpes viruses, Sindbis virus, dengue virus, foot-and-mouth-disease virus, adenoassociated virus, respiratory syncytial virus, papillomavirus and vaccinia virus). It is now clear that for many of these viruses, HS binding represents a tissue culture adaptation with selection for mutations that increase the numbers of positively charged amino acids on the virion surface. These amino acid changes often decrease virulence in vivo. For instance, strains of Sindbis virus that bind HS well replicate optimally in tissue culture, but subcutaneous infection of mice with the same strains leads to lower level viremia and more rapid clearance from the circulation than is observed for strains that do not bind HS and replicate less well in vitro [1]. Thus, a decreased ability to bind HS leads to more efficient viral production in vivo. As Ciarlet and Estes (pp 435–441) point out, a similar situation may exist for sialic acid (SA) binding by rotaviruses. In this case, one of the viral surface proteins (VP8*) binds SA in strains that grow easily in tissue culture, but interaction of a second viral protein (VP5*) with the cell surface is necessary for infection, and interaction with SA is not necessary for rotavirus-induced diarrhea in experimental animals. The need to interact with more than one cell surface molecule, or the use of a co-receptor, is increasingly recognized to be necessary for the entry of many viruses. The presence or absence of a necessary coreceptor can help to explain host range, cell and tissue tropism and varied efficiency of infection. In addition, viruses such as VZV (Arvin, pp 442–449) may require the participation of more than one viral surface protein for efficient attachment and entry. These molecules may also induce cell-signaling events that are necessary for virus infection, as postulated for some rotaviruses.
Virus–receptor interactions and virus entry Strains of viruses that are studied in the laboratory are selected for efficient replication in the tissue culture cells
How viruses traverse the cell membrane to deliver their genomes and initiate infection is an area of active study.
434 Host–microbe interactions: viruses
Enveloped viruses must fuse their lipid membranes with the plasma membrane and this process is best understood for viruses with viral surface proteins that form α-helix coiled coils similar to those formed by cellular fusion proteins. These class I viral fusion proteins are present in orthomyxoviruses, paramyxoviruses, retroviruses and filoviruses. However, not all virus fusion proteins are predicted to form these structures, and Heinz and Allison (pp 450–455) present recent crystallographic studies of the surface fusion glycoproteins of flaviviruses and alphaviruses, both arthropod-borne viruses, that indicate that they represent a new class of viral fusion proteins, class II proteins. These proteins have internal fusion peptides and form trimers without coiled coils and are the first recognized members of this class of proteins.
Virus–host interactions Large DNA viruses such as poxviruses [2], herpesviruses [2,3] (e.g. VZV) and ASFV have a particularly interesting abundance of ‘nonessential’ genes encoding proteins essential for virulence. These proteins may interfere with the immune response by inhibiting major histocompatibility (MHC) antigen expression on infected cells (e.g., the inhibition by VZV proteins of both class I and class II expression), inhibiting cytokine production by infected cells (e.g. cells infected with 5EL or ASFV), or inhibiting cytokine function during the immune response [2,3]. These genes may also determine the fate of the infected cell by inducing or blocking programmed cell death. The genes MGF530 and MGF360 of ASFV are an example of this.
In addition, the outcome of infection often varies with the genetic background of the host, as well as the virus. The ability of the immune system to clear virus from infected cells and tissues is particularly important. ASFV causes persistent nonfatal infection in warthogs and bushpigs, important for the maintenance of the natural cycle, but may cause rapidly fatal disease in domestic swine (Tulman and Rock, pp 456–461). The inability of the host immune system to clear virus can also lead to progressive disease, as illustrated by the human immunodeficiency virus and the hepatitis C virus. Virus persistence in the nervous system can lead to a variety of diseases, as illustrated by Haring and Perlman (pp 462–466) for mouse-hepatitis virusinduced demyelination, and by Carbone et al. (pp 467–475) for Borna-disease-virus-induced neurodegeneration. Diseases may be mediated by the immune response to viral antigens in persistently infected cells or to progressive virusinduced cell loss. Continuing to unravel these complicated virus–host interactions will provide interesting and important insights into the interactive functions of genes from both the virus and the host.
References 1.
Byrnes AP, Griffin DE: Large-plaque mutants of Sindbis virus show reduced binding to heparan sulfate, heightened viremia, and slower clearance from the circulation. J Virol 2000, 74:644-651.
2.
McFadden G, Murphy PM: Host-related immunomodulators encoded by poxviruses and herpesviruses. Curr Opin Microbiol 2000, 3:371-378.
3.
Brander C, Walker BD: Modulation of host immune responses by clinically relevant human DNA and RNA viruses. Curr Opin Microbiol 2000, 3:379-386.