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Coffin JM, Hughes SH, Varmus HE, editors. Retroviruses. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1997.

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Retroviruses.

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Immune Response to Retroviral Infection

The retroviral lifestyle requires that the virus find suitable host cells to establish persistent infection and that it evade the host's immune response. For reasons already discussed, most retroviruses infect some specific subpopulation(s) of cells in the host, often, although not always, precursor cells of the hematopoietic system. This preference may reflect targeting of cells that retain the ability to divide in a mature host. In some cases, the ability of these cells to self-renew may provide a large reservoir of targets that can be repeatedly tapped with minimal damage to the host.

Both arms of the immune system respond to retroviral infections, and it would appear that, depending on the virus in question, both cellular immunity and humoral immunity are important in controlling infection. The role of humoral immunity is relatively direct—antibodies against the Env proteins cause inactivation or clearance of the virus. The cellular immune response affects viral replication indirectly by killing cells that express foreign (viral) proteins. The importance of the humoral response is demonstrated by the fact that certain retroviruses, notably the primate lentiviruses, use extensive glycosylation of their envelope proteins to shield their virions from host antibodies. However, most retroviruses do not kill their host cells, which puts a special premium on the elimination of infected cells and on the cellular immune response. To be effective, the cellular immune system must recognize and kill an infected cell before it can release enough virus to infect at least one more cell.

As with their replication in single cells, there appears to be a division in the way simple and complex viruses interact with the host organism, and it is likely that this reflects different responses of these viruses to the challenge posed by the host's immune system.

In general, simple retroviruses are transmitted early in the development of the host organism (often vertically from mother to offspring), before the immune system of the host is mature. Most of the infected cells survive and continue to divide normally and release virus for the lifetime of the animal. If the infection occurs early enough, the virus can replicate without a strong host immune response (the virus is treated as “self”), and in such cases, viral replication is not controlled by the host. For some simple retroviruses, immune evasion can be assisted by closely related endogenous retroviruses carried by the host. If such endogenous retroviruses are expressed early in development, their expression interferes with the ability of the host to mount an effective immune response against a subsequent challenge by a related exogenous virus. The exogenous virus is shielded (or partially shielded) from the host's immune system by the expression of endogenous virus early in development. This effect creates a strong selective pressure against variation, since it is in the interest of the infecting virus to retain immunological similarity to its endogenous counterpart. In at least some instances, the immune tolerance provided by endogenous viruses may be beneficial to the host, since pathogenic effects (such as a wasting disease often seen in ALV infections) may be mediated by immune killing of infected cells.

Complex retroviruses, in general, infect immune competent adult hosts and must therefore be able to initiate and sustain infection in the face of an active immune response. How immune evasion is accomplished is only poorly understood, but there are probably a number of mechanisms involved. In the case of viruses of the HTLV-BLV genus, at least some of the cells infected soon after transmission are able to persist for a very long time. How such cells evade the T-cell response is not known.

In the case of HIV, and probably all lentiviruses, the infection is not carried forward by persistence of infected cells (although there may be a few of these to confound eradication by antiviral therapy). Rather, infection persists by repeated cycles of infection, cell killing, virus release, and reinfection. In HIV-1 infections, the average length of such cycles is about 2 days. After an initial acute phase of replication, the virus exists in a quasi-steady state until the terminal phase many years later. Because retroviruses have a high mutation rate, repeated rounds of replication leads to a broad array of viral mutants which, in turn, leads to an extensive array of viral variants as the viral population responds to subtle selective pressures.

Replicating in this fashion, lentiviruses respond, at all stages of their life cycle, to both the cellular and humoral immune response. Some lentiviral infections, including those of equine infectious anemia virus, are episodic: There is immune-mediated suppression of infection alternating with periods of extensive replication when fresh immune escape variants arise. Although antigenic variation is clearly involved in the genetic variation characteristic of HIV and SIV infection, its importance as a mechanism of immune avoidance is controversial. Episodic periods of immune escape and suppression do not occur, and it is unclear whether neutralizing antibodies have any significant role in suppression (or, potentially, prevention) of HIV infection. Instead, it is likely that the extensive glycosylation of the primate lentiviral Env proteins, combined with special structural features, renders them nearly invisible to potentially neutralizing antibodies. This implies that immune control of HIV infection (if it can be achieved) rests with the cellular arm of the immune system and that for a vaccine to be effective, a focus on cellular immunity may be required.

Although the dynamic nature of HIV infection makes effective treatment with compounds that inhibit the replication cycle possible, it also engenders the genetic diversity that rapidly reveals itself in the form of mutations that give rise to resistance to all compounds tested to date. All treatments with single agents fail—usually quite rapidly—because of the rapid development of resistance. This puts a particular premium on the use of combinations of therapeutic agents and on therapies that select for viral variants that are less fit than the original wild-type virus. It is worth pointing out, in this context, that the ability of the virus to develop resistance will not be limited to therapeutic treatments involving small molecules; if other strategies (such as those based on genetic modification of the cell) can be developed that block viral replication, then these too will select for resistant variants. In fact, the selection of resistant variants is a simple measure of therapeutic potency.

Copyright © 1997, Cold Spring Harbor Laboratory Press.
Bookshelf ID: NBK19458
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