An important outcome of virus infection in a vertebrate host is the development of a virus-specific immune response triggered by the virus antigens. Regions of antigens known as epitopes bind to specific receptors on lymphocytes, activating cascades of events that result in the immune response.
Lymphocytes are the key cells in specific immune responses. There are two classes of lymphocyte: B lymphocytes (B cells), which develop in the Bursa of Fabricius in birds and in the bone marrow in mammals, and T lymphocytes (T cells), which develop in the thymus. Each lymphocyte is specific for a particular epitope as a result of the presence of epitope-specific receptors on the cell surface. Naive lymphocytes are those that have not encountered their specific epitopes; these cells have surface molecules and circulation patterns in the body distinct from lymphocytes that have previously encountered their epitopes.
Antibodies are glycoproteins of a type known as immunoglobulins. The basic structure of an antibody molecule is shown in Figure 9.3. The molecule is constructed from two 'heavy' and two 'light' polypeptide chains and contains two antigen-binding sites and a region known as the Fc (Fragment crystallizable) region.
There are several classes of immunoglobulin (Ig), the most significant from the point of view of antiviral immunity being IgG and IgM in the blood, and IgA at mucosal surfaces. IgG molecules are monomers with the structure depicted in Figure 9.3, while IgA and IgM molecules are normally dimers and pentamers, respectively.
Antigen-specific antibodies are synthesized by plasma cells, which develop from a B cell after it has been stimulated by interaction between the antigen and a specific immunoglobulin receptor at the cell surface. Antibodies play important roles in several aspects of anti-viral immunity, some of which are summarized in Figure 9.4.
Virus-specific antibody can coat both virions and virus-infected cells, and this may lead to their destruction by a variety of mechanisms. A number of cell types
B cell plasma cell
B cell virus-specific antibody
neutralization of infectivity
Fc receptor enhanced phagocytosis
Figure 9.4 Production of virus-specific antibody and some of its roles in immunity. Virus-specific antibody is secreted by plasma cells derived from B cells that have recognized virus antigens. The antibody may bind to virions and neutralize their infectivity. Antibody-coated virions may be phagocytosed after attachment of antibody Fc regions to receptors on phagocytes.
in the immune system have receptors for the Fc region of IgG (Figure 9.3), allowing these cells to attach to antibody-coated virions and cells. Cell types that have IgG Fc receptors include
• neutrophils and macrophages (these cell types are phagocytes and may phagocytose the antibody-coated materials; they may also kill cells without phagocy-tosing them)
• NK cells (these cells may kill virus-infected cells by insertion of perforins into their membranes).
Another outcome of antibody binding to virus antigens is the activation of complement, which was briefly introduced in Section 4.3.3. This can have a number of anti-viral effects, one of which involves insertion of complement protein complexes into membranes of virus-infected cells and enveloped virions, leading to destruction of these cells and virions. Another anti-viral effect of complement occurs when virions become coated with complement proteins. There are receptors for some of these proteins on neutrophils and macrophages, so phagocytosis of virions is enhanced.
A further effect of antibody binding to virions is neutralization of infectivity, which may occur by a variety of mechanisms.
• Release of nucleic acid from virions. In studies with several viruses, including poliovirus, it was found that antibodies can attach to virions, and then detach leaving empty capsids devoid of their genomes.
• Prevention of virion attachment to cell receptors. Antibody bound to a virion may mask virus attachment sites. Not all virus attachment sites, however, are accessible to antibodies; those of most picor-naviruses are in deep canyons (Section 14.3.1).
• Release of virions that have attached to cell receptors.
• Inhibition of entry into the cell. Antibody coating fusion proteins on an enveloped virion may inhibit fusion of the envelope with a cell membrane.
• Inhibition of genome uncoating. 9.2.2.b T cells
Several days after antigenic stimulation naive or memory T cells develop into effector T cells, of which there are two classes.
• Helper T cells secrete specific cytokines and are characterized by the presence of CD4 molecules at the cell surface. Helper T cells play essential roles in the initiation of immune responses, for example in triggering B cells to develop into antibody-secreting cells and in the maturation of cytotoxic T cells.
• Cytotoxic T cells kill virus-infected cells and are characterized by the presence of CD8 molecules at death of infected cell
Figure 9.5 Kitting of a virus-infected cell by a cytotoxic T cett. A cytotoxic T cell kills a virus-infected cell after the T cell receptors have recognized fragments of virus antigens displayed in association with MHC class I molecules at the cell surface.
the cell surface (Figure 9.5). There is a requirement for viral antigens to be expressed at the surface of target cells. The antigens may be virion surface proteins (e.g. envelope glycoproteins) though often the target antigens are internal virion components, or even nonstructural proteins. Cytotoxic T cells specific for early virus proteins may destroy virus-infected cells long before any infectious virus is produced.
The viral antigens are displayed on the surface of infected cells in association with MHC class I molecules, flagging infected cells for destruction by cytotoxic T cells. Cytotoxic T cells can kill target cells by insertion of proteins (perforins) into their membranes or by inducing apoptosis.
Some viruses, such as herpesviruses, reduce the level of expression of MHC class I molecules at the surface of infected cells, thereby making it more difficult for cytotoxic T cells to recognize infected cells.
The quantity and quality of the adaptive immune response depends on whether or not the host is encountering the virus for the first time. Some B cells and T cells can survive as memory cells long after the first or subsequent encounters. Memory cells have returned to a resting state, from which they can be reactivated if they encounter the same antigen again. These cells are the basis of immunological memory, which can be formed as a result of a natural infection, but also as a result of encountering antigens in vaccines.
The outcome of infection of a vertebrate animal with a virus may depend on whether or not the host has immunological memory of the virus antigens. If immunological memory is present then signs and symptoms of disease are likely to be less severe, or totally absent.
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