IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 16. Antiviral Immunity

IMMUNOPATHOLOGY

The Immune Response to viral Antigens can cause tissue damage

Immune complex-mediated disorders. Immune complexes may appear in various Body Fluids or on Cell surfaces, most frequently during chronic or persistent infections caused, for example, by lymphocytic choriomeningitis virus (LCMV) or hepatitis B virus. In the presence of excess viral antigen, Antibodies lose their ability to neutralize Viruses; instead, they form immune complexes that become deposited in the Kidneys or Blood Vessels of other Organs, triggering inflammatory reactions that can lead to tissue damage, such as Glomerulonephritis (see Chapter 25).

The binding of viruses by non-neutralizing antibodies can sometimes lead to another unusual pathological consequence: As a result of interaction with Fc receptors, these immune complexes are taken up by macrophages, which enhances viral infectivity. This phenomenon can be observed in dengue virus infections. The Pathogenesis of dengue hemorrhagic fever and Shock syndrome is also associated with Fc receptor-mediated interactions of immune complexes that cause hyperactivation of The Complement System.

Host tissue damage by cytotoxic T Cells. In any viral infection, a certain proportion of tissue damage is caused by T-cell activity. In some experimental models, this damage is so substantial that it can result in the death of the animal. A striking example of this is the destruction of cells in the Central Nervous system of mice by cytotoxic T cells during the immune response to LCMV infection (Fig. 16.11). Depletion of T cells rescues the animals from death; thus, it is the T cells, rather than the viruses, that damage Brain tissue. A similar mechanism is presumed to operate in the pathogenesis of chronic active hepatitis in humans.

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Fig. 16.11. Following infection of mice with lymphocytic choriomeningitis virus (LCMV), the outcome of the infection depends on the immune status of the animal. In newborn mice (1), infection leads to chronic virion shedding and immune complex disease, manifesting as glomerulonephritis and vasculitis. In adult animals (2), intracerebral infection causes death as a result of the animal's own T-cell activity; this cause is indicated by the fact that immunosuppression with cyclophosphamide (3) allows the mice to survive, although the infection becomes persistent. The "protective" effect of cyclophosphamide can be abrogated by The transfer of T cells from immune animals (4).

Viruses can infect cells of The Immune System

Some viruses (such as HIV — HUMAN IMMUNODEFICIENCY VIRUS) directly infect lymphocytes and macrophages, exerting a pathogenic effect. In addition, immunocompetent cells serve as a favorable site for viral persistence. Viruses in a non-infectious form are localized within resting leukocytes, whose activation can trigger viral reactivation and the Replication of infectious virions. Examples of viruses that colonize B cells, T cells, and macrophages are shown in Fig. 16.12.

Fig. 16.12. Certain viruses persist indefinitely within immunocompetent cells. Periodically, such infections can lead to pathological consequences, such as cell death (HIV) or malignant transformation (EBV, HTLV-1).

Human immunodeficiency virus infects CD4⁺ T cells. In previous sections, HIV was frequently mentioned as an example—a retrovirus causing Acquired Immunodeficiency Syndrome (AIDS). This infection is characterized by a prolonged asymptomatic period, immune dysfunction, continuous antigenic variation of the virus, its tendency to colonize lymphocytes and cells of myeloid origin, and neuropathological symptoms during the advanced stage of the disease (see Chapter 21).

T cells and macrophages internalize HIV as a result of the viral glycoprotein gp120 binding to the CD4 marker and specific chemokine receptors, CCR3 and CCR5. HIV enters any other antigen-presenting cell in a similar manner. Antiviral antibodies can facilitate this process if The Cell possesses an Fc receptor. Essentially, this represents an alternative pathway for viral entry into phagocytic cells or a mechanism that enhances penetration when CD4 is present in low amounts.

The period of clinical latency in HIV infection varies among patients and can be quite prolonged: in approximately half of infected individuals, HIV infection does not progress to AIDS for 10 years. During this latent period of infection, the pathogen is present in the body as a provirus integrated into the host's genomic DNA, and METABOLISM/31.html">Transcription of the viral DNA does not occur. Viral activation and the initiation of Transcription can be triggered by numerous factors. For example, in vitro exposure of latently infected T-cell cultures to TNF and IL-6 leads to increased production of infectious virions. This phenomenon likely occurs in vivo as well, since monocytes from HIV-infected patients frequently secrete these cytokines in pathologically high amounts. There may exist a cycle of TNF and IL-6 release during a specific phase of which viral Gene transcription is upregulated (Fig. 16.13). Viral replication leads to the infection of an increasing number of cells and the release of ever more cytokines; furthermore, in vitro it is stimulated not only by these but also by other cytokines and lymphokines, as well as mitogens and phorbol esters. Elimination of the virus does not occur for various reasons, including its latent persistence, mutation (causing rapid antigenic drift), and progressive immunological failure.

Fig. 16.13. The glycoprotein gp120 located On the surface of HIV binds to the CD4 molecule on The Plasma Membrane of the lymphocyte, thereby triggering the internalization of the viral particle. HIV can enter macrophages in a similar manner, even though they express significantly fewer CD4 molecules. In this case, viral uptake by macrophages is facilitated by antiviral antibodies that bind to phagocytic cells via Fc receptors. The virus integrates into the host cell genomic DNA and remains latent until specific stimuli (such as cytokines) activate viral gene transcription. Newly formed Viral Particles, after assembly, exit T cells by budding from the plasma membrane or enter intracellular vacuoles of macrophages by the same budding mechanism. Thus, A large number of potentially infectious viral particles can accumulate within macrophages.

Viral infection can trigger autoimmune diseases

Viral pathogenesis of autoimmune diseases involves several mechanisms.

Virus-induced tissue damage. Some viral infections cause tissue damage and a subsequent inflammatory response, resulting in the exposure of previously "hidden" self-antigens, which can then undergo Processing and presentation to the Cells of the immune system. This is observed, for example, in nervous system Infections caused by Theiler's virus (a murine picornavirus) and murine hepatitis virus, where Components of the axonal myelin sheath become targets for antibodies and T cells.

Molecular mimicry. The immune system recognizes as "foreign" an Amino Acid Sequence of a viral protein that is homologous to one of the host's own Proteins. This results in a breakdown of immunological tolerance to sequestered self-antigens, followed by an immune attack against host Tissues (see Chapter 28). A model for this pathogenetic mechanism of autoimmunity can be created experimentally, but proof of its operation in natural viral infections remains limited.

Questions for Structure/133.html">Discussion

■ Through what mechanisms are viruses able to evade the host's defense systems?

■ A young boy is admitted to the clinic suffering from a disseminated herpesvirus infection. What immunotherapy would you prescribe for him, and why?

Introduction/47.html">Further Reading

Borden E.G., Rosenzweig I.В., Byrne G.l. 1987. Interferons: from vires inhibitor to modulator of Amino Acid and Lipid Metabolism. Interferon Res. 7: 591.

Chisari F.V., Ferrari C. 1995. Hepatitis В virus immuno-pathogenesis. Annu. Rev. Immunol. 13: 29-60.

Clements J.E., Gidovin S.L., Montelaro R.C. et al. 1988. Antigenic variation in lentiviral disease. Annu. Rev. Immunol. 6: 139-159.

Doherty P C., Allan W., Eichelberg M. etal. 1992. Roles of а/p and y/8 T cell subsets in viral Immunity. Annu. Rev. 10: 123-151.

Doherty P.C. 1993. Cell-mediated cytotoxicy. Cell. 75: 607.

Gooding L.R. 1992. Virus proteins that counteract host immune defences. Cell 71: 5-7.

Levy J.A. 1993. Pathogenesis of human immunodeficiency virus infection. Microbiol. Rev. 57: 183-289.

Mims C.A. 1986. Interactions of viruses with the immune system. Clin. Exp. Immunol. 66: 1-16.

Nash A.A., Cambouropoulos P. 1993. The immune response to Herpes simplex virus. Semin. Virol. 4: 181-186.

Oldstone M.B.A. 1987. Molecular mimicry and autoimmune disease. Cell 50: 819-820.

Ramsay A.J. 1993. A case for cytokines as effector molecules in the resolution on virus infection. Immunol. Today 14: 155.

Sissons J.G., Oldstone M.B.A. 1980. Antibody-mediated destruction of virus-infected cells. Adv. Immunol. 31: 1.

Smith G.A. 1994. Virus strategies for evasion of the host response to infection. Trends. Microbiol. 2: 81-88.