Adaptive Immunity to Viruses

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Adaptive immunity against viral infections is mediated by antibodies, which block virus binding and entry into

Virus

Microbial product (PAMP)

Pattern recognition receptor

Transcription factor

Virus

FIGURE 15-7 Mechanisms of induction of type I interferons by viruses. Viral nucleic acids and proteins are recognized by several cellular receptor families (TLRs and the family of cytosolic RIG-like receptors, or RLRs, which include MDA-5, RIG-I, DAI and others), which activate transcription factors (the IRF proteins) that stimulate the production of type I interferons, IFN-a and IFN-|3. This process and the actions of interferons are described in more detail in Chapter 4.

FIGURE 15-7 Mechanisms of induction of type I interferons by viruses. Viral nucleic acids and proteins are recognized by several cellular receptor families (TLRs and the family of cytosolic RIG-like receptors, or RLRs, which include MDA-5, RIG-I, DAI and others), which activate transcription factors (the IRF proteins) that stimulate the production of type I interferons, IFN-a and IFN-|3. This process and the actions of interferons are described in more detail in Chapter 4.

host cells, and by CTLs, which eliminate the infection by killing infected cells (see Fig. 15-6). The most effective antibodies are high-affinity antibodies produced in T-dependent germinal center reactions (see Chapter 11). Antibodies are effective against viruses only during the extracellular stage of the lives of these microbes. Viruses may be extracellular early in the course of infection, before they infect host cells, or when they are released from infected cells by virus budding or if the cells are killed. Antiviral antibodies bind to viral envelope or capsid antigens and function mainly as neutralizing antibodies to prevent virus attachment and entry into host cells. Thus, antibodies prevent both initial infection and cell-to-cell spread. Secreted antibodies of the IgA isotype are important for neutralizing viruses within the respiratory and intestinal tracts. Oral immunization against poliomyelitis works by inducing mucosal immunity. In addition to neutralization, antibodies may opso-nize viral particles and promote their clearance by phagocytes. Complement activation may also participate in antibody-mediated viral immunity, mainly by promoting phagocytosis and possibly by direct lysis of viruses with lipid envelopes.

The importance of humoral immunity in defense against viral infections is supported by the observation that resistance to a particular virus, induced by either infection or vaccination, is often specific for the serologic (antibody-defined) type of the virus. An example is influenza virus, in which exposure to one serologic type does not confer resistance to other serotypes of the virus.

Neutralizing antibodies block viral infection of cells and spread of viruses from cell to cell, but once the viruses enter cells and begin to replicate intracellularly, they are inaccessible to antibodies. Therefore, humoral immunity induced by previous infection or vaccination is able to protect individuals from viral infection but cannot by itself eradicate established infection.

Elimination of viruses that reside within cells is mediated by CTLs, which kill the infected cells. As we have mentioned in previous chapters, the principal physiologic function of CTLs is surveillance against viral infection. Most virus-specific CTLs are CD8+ T cells that recognize cytosolic, usually endogenously synthesized, viral pep-tides presented by class I MHC molecules. If the infected cell is a tissue cell and not a professional antigen-presenting cell (APC), such as a dendritic cell, the infected cell may be phagocytosed by the dendritic cell, which processes the viral antigens and presents them to naive CD8+ T cells. This process of cross-presentation, or cross-priming, was described in Chapter 6 (see Fig. 6-20). Full differentiation of CD8+ CTLs often requires cytokines produced by CD4+ helper cells or costimulators expressed on infected cells (see Chapter 9). As discussed in Chapter 9, CD8+ T cells undergo massive proliferation during viral infection, and most of the proliferating cells are specific for a few viral peptides. Some of the activated T cells differentiate into effector CTLs, which can kill any infected nucleated cell. The antiviral effects of CTLs are mainly due to killing of infected cells, but other mechanisms include activation of nucleases within infected cells that degrade viral genomes and secretion of cytokines such as IFN-y, which activates phagocytes and may have some antiviral activity.

The importance of CTLs in defense against viral infection is demonstrated by the increased susceptibility to such infections seen in patients and animals deficient in T lymphocytes and by the experimental observation that mice can be protected against some virus infections by adoptive transfer of virus-specific, class I-restricted CTLs. Furthermore, many viruses are able to alter their surface antigens, such as envelope glycoproteins, and thus escape attack by antibodies. However, infected cells may produce some viral proteins that are invariant, so that CTL-mediated defense remains effective against such viruses.

In latent infections, viral DNA persists in host cells but the virus does not replicate or kill infected cells. Latency is often a state of balance between infection and the immune response. CTLs are generated in response to the virus that can control the infection but not eradicate it. As a result, the virus persists in infected cells, sometimes for the life of the individual. Any deficiency in the host immune response can result in reactivation of the latent infection, with expression of viral genes that are responsible for cytopathic effects and for spread of the virus. These cytopathic effects may include lysis of infected cells or uncontrolled proliferation of the cells. Such latent infections are common with Epstein-Barr virus and several other DNA viruses of the herpesvirus family.

In some viral infections, tissue injury may be caused by CTLs. An experimental model of a disease in which the pathology is due to the host immune response is lymphocytic choriomeningitis virus (LCMV) infection in mice, which induces inflammation of the spinal cord meninges. LCMV infects meningeal cells, but it is noncy-topathic and does not injure the infected cells directly. The virus stimulates the development of virus-specific CTLs that kill infected meningeal cells during a physiologic attempt to eradicate the infection. Therefore, meningitis develops in normal mice with intact immune systems, but T cell-deficient mice do not develop disease and instead become carriers of the virus. This observation appears to contradict the usual situation, in which immu-nodeficient individuals are more susceptible to infectious diseases than normal individuals are. Hepatitis B virus infection in humans shows some similarities to murine LCMV in that immunodeficient persons who become infected do not develop the disease but become carriers who can transmit the infection to otherwise healthy persons. The livers of patients with acute and chronic active hepatitis contain large numbers of CD8+ T cells, and hepatitis virus-specific, class I MHC-restricted CTLs can be isolated from liver biopsy specimens and propagated in vitro.

Immune responses to viral infections may be involved in producing disease in other ways. A consequence of persistent infection with some viruses, such as hepatitis B, is the formation of circulating immune complexes composed of viral antigens and specific antibodies (see Chapter 18). These complexes are deposited in blood vessels and lead to systemic vasculitis. Some viral proteins contain amino acid sequences that are also present in some self antigens. It has been postulated that because of this "molecular mimicry," antiviral immunity can lead to immune responses against self antigens.

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