induce interferon production and are not susceptible to its inhibitory effects. This represents the extreme example of immunologic tolerance due to molecular mimicry There seems to be no mechanism whereby the host can restrict the replication and pathologic effects of these agents.

True viruses are, of course, immunogenic. Some have evolved strategies for evading neutralization by the antibody they elicit.

Cell Fusion Lentiviruses (e.g., HIV), paramyxoviruses (e.g., measles virus), and herpesviruses (e.g., cytomegalovirus) cause adjacent cells to fuse together, enabling the viral genome to spread contiguously from cell to cell without ever being exposed to antibody.

Blocking by Nonneutralizing Antibodies Very high titers of antibody are characteristic of many chronic viral infections, so much so that virus-antibody and antigen-antibody complexes accumulate at the basement membranes of renal glomeruli and other sites, causing a variety of immune complex diseases. Yet the virus is not eliminated. Much of this antibody may be directed against viral proteins or epitopes that are not relevant to neutralization; by binding to the virion nonneutralizing antibodies can block the attachment of neutralizing antibody, by steric hindrance.

Antigen Decoy The chronic carrier state in hepatitis B is marked by the production of a huge excess of noninfectious particles of HBsAg, which may serve as a decoy to mop up neutralizing antibody. Perhaps other chronic infections are also sustained by this strategy.

Immunosuppressive Epitopes The HIV envelope glycoprotein, and the equivalent in other retroviruses, contains a sequence that inhibitsT-cell proliferation in response to antigen.

Antigenic Drift Mutations emerge with unusual frequency in retroviruses because their reverse transcriptase is error-prone. During the prolonged incubation period of the slow infections characteristic of lentiviruses such as equine infectious anemia, visna/maedi in sheep, and HIV in humans, there is ample time for antigenic drift to occur in the presence of neutralizing antibody.

Reduced Display of Antigen on Plasma Membrane

An equally dazzling variety of strategies help viruses to persist by diminishing the display of antigen on the cell surface, as seen by T lymphocytes or by antibody.

Limitation of Viral Gene Expression As discussed above, latency is characterized by the production of very few viral proteins, and hence the cell membrane contains little of interest to passing T cells or antibodies. For example, in HSV latency the neuron displays no viral antigen at all. This protects the cell not only against cytotoxic T cells but also against lysis by antibody-complement or by antibody-dependent cell-mediated cytotoxicity.

Antibody-Induced Removal of Antigen from Plasma Membrane Antibody, being at least divalent, can bridge antigen molecules in membranes, bringing about "capping" followed by endocytosis or shedding of the antigen. The phenomenon is readily demonstrable in vitro on "carrier cultures" of cells persistently infected with budding viruses and has been postulated to play a role in SSPE, in which antibody also down-regulates transcription of the measles viral genome.

Down-regulation of MHC Antigen Expression Because CD8+ T cells see viral peptides bound to MHC class I antigen (and CD4+ T cells see them in the context of MHC class II), viral persistence is presumably favored by reduction of the concentration of MHC molecules on the cell surface. Adenoviruses encode an early protein that binds to newly synthesized MHC class I antigen, preventing its normal processing thus reducing its cell surface expression.

Down-regulation of Cell Adhesion Molecules As discussed above, Burkitt's lymphoma cells, which carry the EB virus genome, display reduced amounts of the adhesion molecules ICAM-1 and LFA-3, and therefore bind T cells with lower affinity.

Immunosuppression by Infection of Effector Cells

Many viruses can replicate productively or abortively in cells of the reticuloendothelial system, and it is noteworthy that these cells are often implicated in persistent infections. Lymphocytes and monocytes/macrophages represent tempting targets lor any virus, in that they move teadily throughout the body and can seed virus to any organ, as well as being the key players in the immune response. To render them impotent would ensure persistence. The extreme example of destruction of the body's immune system is provided by HIV, which replicates in CD4+ T lymphocytes and cells of the monocyte/macrophage series. Virtual elimination of helper T cells from the body results in such profound depression of the immune response that the patient dies from intercurrent infections with other opportunistic pathogens, or from cancer.

Abrogation of Lymphocyte Function Numerous other viruses temporarily induce generalized immunosuppression by abrogating the function of one particular arm of the immune response. For example, measles virus suppresses Th, cells (DTH). Epstein-Barr virus induces polyclonal activation of B cells which diverts the immune system to irrelevant activity. And so on.

Abrogation of Macrophage Function In many chronic viral infections the virus grows mainly in reticuloendothelial tissue, especially in macrophages. This may impair several key immunologic functions, notably phagocytosis, antigen processing, and presentation to T cells.

Evasion of Cytokines

Interferons are induced by infection with viruses and display a wide range of antiviral as well as immunomodulatory activities (described in Chapters 5 and 7). However, at least some viruses have evolved genes that in one way or another sabotage the specific antiviral action of the key effector molecules known as interferon-regulated proteins (see Chapter 5), whereas others can counter other antiviral cytokines (e.g., an adenovirus gene product partially protects infected cells against tumor necrosis factor).

Induction of Immunologic Tolerance

The probability of an acute infection progressing to chronicity is strongly age-related. In particular, congenital transmission to the neonate, whether transplacental or perinatal, greatly enhances the likelihood. Prolonged chronicity is the rule rather than the exception following congenital infections with hepatitis B virus, rubella virus, cytomegalovirus, parvovirus B19, HTLV-1, or HIV. Presumably this reflects immunologic immaturity/nonresponsive-ness. No B-cell tolerance is demonstrable, but there is often a degree of T-cell unresponsiveness to the virus. In the well-studied lymphocytic choriomeningitis (LCM) virus infection of mice, infant mice infected naturally in utero do not mount a T-cell-mediated immune response to the virus; the fact that this is reversible indicates that it is due not the deletion of LCM virus-reactive T-cell clones during embryonic life, but rather to clonal anergy or production of suppressor T cells.

Sequestration in Sanctuaries

A striking proportion of persistent infections involve the central nervous system. The brain is insulated from the immune system to some degree by the blood-brain barrier and, further, neurons express very little MHC antigen on their surface, thereby conferring some protection against lysis by cytotoxic T lymphocytes. Herpesviruses, polyomaviruses, and lentiviruses are good examples HIV is relatively protected not only in the brain but also in the epididymis. Certain other viruses grow in epithelial cells on luminal surfaces.

Examples of Reactivation of Persistent Viral Infections in Humans

Examples of Reactivation of Persistent Viral Infections in Humans




Clinical severity

Old age

Varicella virus

Rash of shingles



Polyomavirus JC, BK


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