Cell-mediated immunity, antibody, complement, phagocytes, and interferons and other cytokines are all involved in the response to viral infections and may alone or in concert be responsible for recovery, depending on the particular host-virus combination (see Fig 8-4).
Role of T Lymphocytes
Lymphocytes and macrophages normally predominate in the cellular infiltration of virus-infected tissues; in contrast to bacterial infections, poly-
morphonuclear leukocytes are not at all plentiful Depletion of T cells by neonatal thymectomy or antilymphocyte serum treatment increases the susceptibility of experimental animals to most viral infections; for example, T-cell-depleted mice infected with ectromelia virus fail to show the usual inflammatory mononuclear cell infiltration in the liver, develop extensive liver necrosis, and die, in spite of the production of antiviral antibodies and interferon. Virus liters in the liver and spleen of infected mice can be greatly reduced by adoptive transfer of immune T cells taken from recovered donors; this process is class I MHC restricted, implicating Tc cells, and is lifesaving.
Another experimental approach is to ablate completely all immune potential, then add back one or more of the separate components of the immune system. Using mice treated in this way, virus-primed cytotoxic T lymphocytes of defined function and specificity, cloned in culture then transferred to infected animals, have been shown to save the lives of mice infected with lymphocytic choriomeningitis virus, influenza virus, or several other viruses. Generally, greater protection is conferred by CD8+ T cells than by CD4+ T cells. Moreover, transgenic mice lacking CD8+ T cells suffer higher morbidity and mortality than normal mice following virus challenge. Nevertheless, CD4+ T cells have been shown to play a significant role in recovery, as do the cytokines they secrete, notably interferon 7 and IL-2.
Although T-cell determinants and B-cell epitopes on surface proteins of viruses sometimes overlap, the immunodominant Tc determinants are often situated on the relatively conserved proteins located in the interior of the virion, or on nonstructural virus-coded proteins that occur only in virus-infected cells. Hence T cell responses are generally of broader specificity than neutralizing antibody responses and display cross-reactivity between strains and serotypes. When the gene encoding a protein that fails to elicit any neutralizing antibody (e.g., the NP, M, or NS protein of influenza virus) is incorporated into the genome of vaccinia virus, the T cells elicited following infection with the construct can adoptively transler to naive mice complete protection against challenge with influenza virus.
Congen ita! Immunodeficiencies
The approach least subject to laboratory artifact is simple clinical observation of viral infections in experimental animals or children suffering from primary immunodeficiencies; such studies indicate a key role for T lymphocytes in recovery from generalized viral infections. Animals or humans with severe T-cell deficiencies due to thymic aplasia, lymphoreticular neoplasms, or chemical immunosuppression show increased susceptibility to herpesviruses and to many other viral infections that cannot be controlled by antibody. Perhaps the most informative example is that of measles in infants with thymic aplasia. In these T-cell-deficient infants there is no sign of the usual measles rash but rather an uncontrolled and progressive growth of virus in the respiratory tract, leading to fatal pneumonia. This reveals two aspects of the role of T cells; evidently, in the normal child, the T-cell-mediated immune response controls infection in Ihe lung and plays a vital role in the development of the characteristic skin rash as well.
The role of NK cells in recovery from viral infection is not yet certain. Athymic mice, which have almost no T cells but normal numbers of NK cells, usually die if infected with viruses that produce generalized viral infections. On the other hand, "beige" mice, which have substantially reduced NK cell activity, or normal mice depleted of NK cells by treatment with NK-specific antibody, show increased replication of some viruses but not others. The NK cells probably represent an innate defense mechanism of particular relevance in the early stage of primary virus infections, but they are less crucial than either T cells or antibody in clearing the infection and play no role in the establishment of immunologic memory.
In generalized diseases characterized by a viremia in which virions circulate free in the plasma, circulating antibody plays a significant role m recovery. Unlike those with a T-cell deficit, children with severe primary agammaglobulinemia recover normally from measles or varicella but are about 10,000 times more likely than normal children to develop paralytic disease after vaccination with live attenuated poliovirus vaccine. They have normal cell-mediated immune and interferon responses, normal phagocytic cells and complement, but cannot produce antibody, which is essential if poliovirus spread to the central nervous system via the bloodstream is to be prevented.
Although there is reasonably good evidence that antibody plays a key role in recovery from picornavirus, togavirus, flavivirus, and parvovirus infections, it does not necessarily follow that the antibody is acting solely by neutralizing virions. Indeed it has been shown that certain nonneutrahzing monoclonal antibodies can save the lives of mice, presumably by antibody-dependent cell-mediated cytotoxicity or antibody-complement-mediated lysis of infected cells, or by opsonization of virions for macrophages
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