病毒学双语版课件Cha-1.ppt

Academic Press, 2000.,Pathogenesis,Learning Objectives: On completing this session, you should be able to: Explain the concept of pathogenesis in the context of virus infections. Discuss the molecular basis for virus-induced immunodeficiency (including AIDS) & cell transformation by viruses. Understand the ways in which virus infection may result in cellular injury., Academic Press, 2000.,Pathogenicity,Pathogenicity, the capacity of one organism to cause disease in another, is a complex & variable phenomenon. At the simplest level there is the question, what is disease? An all-embracing definition would be that it is a departure from the normal physiological parameters of an organism. This could range from a transient & very minor condition such as a slightly elevated temperature or rather subjective feelings of lethargy to chronic pathologic conditions which eventually result in death. Any of these conditions may result from a large number of internal or external sources. However, there is rarely one single factor which causes a disease. Most disease states are multi-factorial at one level or another., Academic Press, 2000.,Virus Diseases,Two components are involved: the direct effects of virus replication the effects of bodily responses to the infection The course of any virus infection is determined by a delicate & dynamic balance between the host & the virus, as is the extent & severity of virus pathogenesis. In some virus infections, most of the pathologic symptoms observed are attributable not to virus replication, but to the side-effects of the immune response. Inflammation, fever, headaches & skin rashes are not usually caused by viruses themselves, but by the cells of the immune system due to the release of potent chemicals such as interferons & interleukins. In the most extreme cases, none of the pathologic effects of certain diseases are caused directly by the virus, except that its presence stimulates the activation of the immune system., Academic Press, 2000.,Virus Pathogenesis,Virus pathogenesis is an abnormal & fairly rare situation - the majority of virus infections are silent & do not result in outward signs of disease. It is sometimes said that viruses would disappear if they killed their hosts - this is not necessarily true. It is possible to imagine viruses with a hit-and-run strategy, moving quickly from one dying host to the next & relying on continuing circulation for their survival. Nevertheless, there is a clear tendency for viruses not to injure their hosts if possible. Ideally, a virus would not even provoke an immune response from its host, or at least be able to hide to avoid the effects. Three major aspects of virus pathogenesis must be considered: direct cell damage resulting from virus replication, damage resulting from immune activation or suppression, & cell transformation caused by viruses., Academic Press, 2000.,Mechanisms of Cellular Injury,Virus infection results in a number of changes which are detectable by visual or biochemical examination of infected cells. These changes result from the production of virus proteins & nucleic acids, but also from alterations to the biosynthetic capabilities of cells. Intracellular parasitism by viruses sequesters cellular apparatus such as ribosomes & raw materials which would normally be devoted to synthesizing molecules required by the cell. Eukaryotic cells must carry out constant macromolecular synthesis, whether they are growing & dividing or in a state of quiescence., Academic Press, 2000.,Mechanisms of Cellular Injury,A growing cell clearly needs to manufacture more proteins, more nucleic acids & more of all of its myriad components to increase its size before dividing. The function of all cells is regulated by controlled expression of their genetic information & the subsequent degradation of the molecules produced. Such control relies on a delicate & dynamic balance between synthesis & decay which determines the intracellular levels of all the important molecules in the cell. This is particularly true of the control of the cell cycle, which determines the behaviour of dividing cells., Academic Press, 2000.,Mechanisms of Cellular Injury,A number of common phenotypic changes can be recognized in virus-infected cells. These changes are often referred to as the cytopathic effects (c.p.e.) of a virus & include: 1) Altered shape 2) Detachment from the substrate 3) Lysis 4) Membrane fusion 5) Membrane permeability 6) Inclusion bodies 7) Apoptosis, Academic Press, 2000.,Shutoff,A number of viruses which cause cell lysis exhibit a phenomenon known as shutoff early in infection. Shutoff is the sudden & dramatic cessation of most host cell macromolecular synthesis. In poliovirus-infected cells, this is the result of production of the virus 2A protein. This molecule is a protease which cleaves the p220 component of eIF-4F, a complex of proteins required for cap-dependent translation of messenger RNAs by ribosomes. Since poliovirus RNA does not have a 5 methylated cap but is modified by the addition of the VPg protein, virus RNA continues to be translated. In poliovirus-infected cells, the dissociation of mRNAs & polyribosomes from the cytoskeleton can be observed & this is the reason for the inability of the cell to translate its own messages. A few hours after translation ceases, lysis of the cell occurs., Academic Press, 2000.,Cell Damage by Adenoviruses,In the case of adenoviruses, the penton protein (part of the virus capsid) has a toxic effect on cells. Although its precise action on cells is not known, addition of purified penton protein to cultured cells results in their rapid death. Toxin production by pathogenic bacteria is a common phenomenon, but this is the only well-established case of a virus-encoded molecule with a toxin-like action. The adenovirus E3-11.6K protein is synthesized in small amounts from the E3 promoter at early stages of infection & in large amounts from the major late promoter at late stages of infection. E3-11.6K is required for the lysis of adenovirus-infected cells & the release of virus particles from the nucleus., Academic Press, 2000.,Membrane Fusion,Membrane fusion is the result of virus-encoded proteins required for infection of cells, typically the glycoproteins of enveloped viruses. One of the best known examples of such a protein comes from Sendai virus (a paramyxovirus), which has been used to induce cell fusion during the production of monoclonal antibodies. At least nine of the eleven known herpes simplex virus (HSV/HHV-1) glycoproteins have been characterised regarding their role in virus replication. A number of these proteins are involved in fusion of the virus envelope with the cell membrane & also in cell penetration. Production of fused syncytia is a common feature of HSV infection., Academic Press, 2000.,Cell Fusion by HIV,Infection of CD4+ cells with some but not all isolates of HIV causes cell-cell fusion & the production of syncytia or giant cells. The protein responsible for this is the transmembrane envelope glycoprotein of the virus (gp41) & the domain near the amino terminus responsible for this fusogenic activity has been identified by molecular genetic analysis. Because HIV infects CD4+ cells & it is the reduction in the number of these crucial cells of the immune system which is the most obvious defect in AIDS, it was initially believed that direct killing of these cells by the virus was the basis for the pathogenesis of AIDS. Although direct cell killing by HIV undoubtedly occurs in vivo, it is now believed that the pathogenesis of AIDS is considerably more complex. Many animal retroviruses also cause cell killing & in most cases, it appears that the envelope protein of the virus is required, although there may be more than one mechanism involved., Academic Press, 2000.,Cell Fusion by HIV, Academic Press, 2000.,Viruses & Immunodeficiency,At least two groups of viruses, herpesviruses & retroviruses, directly infect the cells of the immune system. This has important consequences for the outcome of the infection & for the immune system of the host. Herpes simplex virus (HSV) establishes a systemic infection, spreading via the bloodstream in association with platelets, but does not show particular tropism for cells of the immune system. However, Herpes saimirii & Mareks disease virus are herpesviruses which cause lymphoproliferative diseases (but not clonal tumours) in monkeys & chickens, respectively. The most recently discovered human herpesviruses, human herpesvirus-6 (HHV-6), HHV-7 & HHV-8 all infect lymphocytes., Academic Press, 2000.,Infection of Immune cells by Herpesviruses,Epstein-Barr virus infection of B-cells leads to immortalization & proliferation, resulting in glandular fever or mononucleosis, a debilitating but benign condition. EBV was first identified in a lymphoblastoid cell line derived from Burkitts lymphoma and, in rare instances, EBV infection may lead to the formation of a malignant tumour. While some herpesviruses such as HSV are notably cytopathic, most of the lymphotropic herpesviruses do not cause a significant degree of cellular injury. Infection of the delicate cells of the immune system may perturb their normal function. Because the immune system is internally regulated by complex networks of interlinking signals, relatively small changes in cellular function can result in its collapse. Alteration of the normal pattern of production of cytokines could have profound effects on immune function. The trans-regulatory proteins involved in the control of herpesvirus gene expression may also affect the transcription of cellular genes - the effects of herpesviruses on immune cells are more complex than just cell killing., Academic Press, 2000.,Retrovirus Pathogenesis,Retroviruses cause a variety of pathogenic conditions including paralysis, arthritis, anaemia & malignant cellular transformation. A significant number of retroviruses infect the cells of the immune system. Although these infections may lead to a diverse array of diseases & haematopoetic abnormalities such as anaemia & lymphoproliferation, the most commonly recognized consequence of retrovirus infection is the formation of lymphoid tumours. However, some degree of immunodeficiency, ranging from very mild to quite severe, is a common consequence of the interference with the immune system resulting from the presence of a lymphoid or myeloid tumour., Academic Press, 2000.,Acquired Immunodeficiency Syndrome (AIDS),The most prominent aspect of virus-induced immunodeficiency is acquired immunodeficiency syndrome (AIDS), a consequence of infection with Human immunodeficiency virus (HIV), a member of the genus Lentivirus of the Retroviridae. There are a number of similar lentiviruses which cause immunodeficiency diseases in animals. Unlike infection by other types of retrovirus, HIV infection does not directly result in the formation of tumours. Some tumours such as B-cell lymphomas are sometimes seen in AIDS patients but these are consequence of the lack of immune surveillance which is responsible for the destruction of tumours in healthy individuals. The clinical course of AIDS is long & very variable. A great number of different abnormalities of the immune system are seen in AIDS. As a result of the biology of lentivirus infections, the pathogenesis of AIDS is highly complex., Academic Press, 2000.,AIDS Pathogenesis,It is still not completely clear how much of the pathology of AIDS is caused directly by the virus & how much is caused by the immune system. There are numerous models that have been suggested to explain how HIV causes immunodeficiency. These mechanisms are not mutually exclusive & it is probable that the underlying loss of CD4+ cells in AIDS is multifactorial., Academic Press, 2000.,Direct Cell Killing:,This was the earliest mechanism suggested, based on the behaviour of laboratory isolates of HIV. Cell fusion resulting in syncytium formation is one of the major mechanisms of cell killing by HIV in vitro. However, different isolates of HIV vary considerably in the extent to which they promote the fusion of infected cells. Subsequent experiments suggested there may not be sufficient virus present in AIDS patients to account for all the damage seen, although killing of CD4+ cells may contribute to the overall pathogenesis of AIDS in some circumstances. Recently, it has become clear that up to half of the CD4+ cells in the body may be infected with HIV, so the idea of direct cell killing has been re-examined, but in light of induction of apoptosis rather than by cell fusion., Academic Press, 2000.,Indirect Killing of HIV-Infected Cells:,Indirect effects of infection, e.g. disturbances in cell biochemistry & cytokine production, may also affect the regulation of the immune system. However, the expression of virus antigens on the surface of infected cells leads to indirect killing by the immune system - effectively a type of autoimmunity. The extent of this activity is dependent on the virus load & replication kinetics in infected individuals., Academic Press, 2000.,Antigenic Diversity,This theory proposes that the continual generation of new antigenic variants eventually swamps & overcomes the immune system, leading to its collapse. There is no doubt that new antigenic variants of HIV constantly arise during the long course of AIDS because of the low fidelity of reverse transcription. It is envisaged that there might be a ratchet effect, with each new variant contributing to the slight but irreversible decline in immune function. Because of the way virus infections are handled by the immune system, it is probable that variation of T-cell epitopes on target proteins recognized by CTL are more important than B-cell epitopes which generate the antibody response to a foreign antigen. Recently, it has been shown that there is a simple relationship between virus load & survival time, & that a patient can withstand only 1,300 “viral years“ of HIV (i.e. copies of the virus genome/ml x survival time in years)., Academic Press, 2000.,Antigenic Diversity of HIV, Academic Press, 2000.,T-Cell Anergy:,Anergy is an immunologically unresponsive state in which lymphocytes are present but not functionally active. This is usually due to incomplete activation signals & may be an important regulatory mechanism in the immune system, e.g. tolerance of self antigens. In AIDS, anergy could be induced due to HIV infection, e.g. interference with cytokine expression. There is experimental in vitro evidence that gp120-CD4 interactions result in anergy due to interference with signal transduction. Many AIDS patients are anergic, i.e. fail to mount a delayed-type hypersensitivity (DTH) response to skin-test antigens. Impaired DTH responses are directly related to decreasing CD4+ T-lymphocyte counts. However, there is no strong evidence that this phenomenon is directly related to any aspect of HIV infection in vivo rather than to general depletion of immune functions., Academic Press, 2000.,Apoptosis:,Like T-cell anergy, apoptosis could potentially be induced in large numbers of uninfected cells by factors released from a much smaller number of HIV-infected cells. In addition to clonal deletion as a normal part of the evolution of the T-cell repertoire, apoptosis may be induced following T-cell activation as a negative regulatory mechanism to control the strength & duration of the immune response. HIV infection of T-cells induces an activated phenotype, e.g. surface expression of CD45 & HLA-DR markers, which suggests that these cells may be inevitably doomed due to activation of the apoptosis pathway. Because HIV establishes a persistent infection, it is by no means clear that apoptosis has an entirely negative effect - induction of cell death may well limit virus production & slow down the course of infection. Several HIV proteins have been identified as both inducers & repressors of apoptosis under various circumstances. However, the proportion of CD4+ T cells in the later stages of apoptosis is about twofold higher in HIV-1 infected individuals than in uninfected people., Academic Press, 2000.,Superantigens:,Superantigens are molecules which short-circuit the immune system, resulting in massive activation of T-cells rather than the usual, carefully controlled response to foreign antigens. It is believed that they do this by binding to both the variable region of the b-chain of the T-cell receptor (Vb) & to MHC class II molecules, cross-linking them in a non-specific way. This results in polyclonal T-cell activation rather than the usual situation where only the few clones of T-cells responsive to a particular antigen presented by the MHC class II molecule are activated. The over-response of the immune system produced results in autoimmunity as whole families of T-cells which bind superantigens are activated, & immunosuppression as the activated cells are killed by other activated T-cells or undergo apoptosis. No superantigen has been conclusively identified in HIV, despite intensive investigation, thus the practical relevance of superantigens in AIDS is in doubt., Academic Press, 2000.,Superantigens:, Academic Press, 2000.,TH1/TH2 Imbalance:,Immunological theory suggests that there are two types of CD4+ T-helper (TH) cell: TH1 cells which promote the cell mediated response & TH2 cells which promote the humoral response. This theory suggests that early in HIV infection, TH1-responsive T-cells predominate & are effective in controlling (but not eliminating) the virus. At some point, a (relative) loss of the TH1 response occurs & TH2 HIV-responsive cells predominate. The hypothesis is therefore that the TH2-dominated humoral response is not effective at maintaining HIV replication at a low level & the virus load builds up, resulting in AIDS. Although this is largely a theoretical proposal which has not been proved, this thinking