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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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Immunological and Pharmacological Approaches to the Control of Retroviral Infections

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Prevention of retroviral infections and their management in infected hosts are of great practical importance. In particular, the AIDS epidemic has brought this issue to the forefront, although it is important to remember that other pathogenic retroviruses are responsible for important clinical diseases in humans (e.g., HTLV-1), agricultural animals (e.g., ASV/ALV, REV, BLV, EIAV, visna/maedi, and CAEV), and pets (e.g., FeLV and FIV).

The traditional approach to managing viral diseases has been to prevent infection through the use of vaccines. As discussed in the first section of this chapter, traditional vaccines are intended to induce prophylactic immunity that will protect vaccinated individuals when they subsequently encounter the pathogen. Successful immunization of some (but not necessarily all) potentially infectable individuals in a population has been effective in controlling many viral diseases (e.g., the Salk and Sabin vaccines for poliomyelitis). Unvaccinated individuals in such a population are also less likely to become infected due to “herd immunity”—the risk of exposure is reduced because most individuals in the group are immune and thus unlikely to become productively infected.

Prophylactic vaccinations have been the predominant method for managing viral diseases, because until quite recently, relatively little could be done to treat individuals after they were infected. Although attempts are being made to develop therapeutic vaccines for human immunodeficiency virus type 1 (HIV-1), this is quite a difficult problem and there have been no reports as yet of a successful therapeutic vaccine. Classical antibiotics such as those developed against bacterial and fungal infections have not been particularly effective in treating viral infections. Antibiotics typically target biochemical differences between the metabolic machinery of the infecting agent and the cells of the host. For instance, streptomycin specifically inhibits bacterial protein synthesis by binding to bacterial ribosomes, but it does not affect the protein synthesis machinery of higher eukaryotes. Since viruses use so much of the host-cell machinery for their replication, it has been much more difficult to develop drugs that specifically inhibit viral replication without harming the host. However, molecular studies of viral replication have led to the development of antiviral compounds that specifically inhibit processes carried out by virus-encoded proteins. Because these drugs target viral proteins, they have limited detrimental effects on uninfected cells. For instance, the nucleoside analogs acyclovir and gancyclovir can be used to effectively beat human herpes simplex virus and cytomegalovirus infections because they are selectively phosphorylated by viral thymidine kinase and incorporated into viral DNA. Most of the work on antiretroviral compounds has focused on HIV-1. A number of important anti-HIV-1 drugs exist that inhibit either the viral protease or reverse transcriptase (RT), and these inhibitors are discussed in the second part of this chapter.

Retroviral infection poses several problems that have complicated the development of vaccines or antiviral compounds. First, retroviruses have a relatively high rate of mutation. If, in the natural host, this is coupled with rapid turnover of the virus and extensive replication, which occurs in HIV-1 infections, then viral variants emerge rapidly.

There is an additional level of complexity in host-virus systems in which the host harbors and expresses endogenous viruses that are closely related to the exogenous viruses they subsequently encounter. If the endogenous viruses are expressed early in development, this expression will induce partial immunological tolerance in the animal. In this sense, the endogenous viruses shelter the exogenous viruses from the host's immune system. It is important to distinguish systems in which such immunological shelter is known to exist (i.e., avian leukemia viruses [ALVs] in chickens) from systems in which the host harbors no closely related endogenous virus (i.e., HIV-1 in humans). Different strains of chickens harbor (and express) different arrays of endogenous viruses; it should not be surprising that the degree of tolerization varies considerably. However, in general, the behavior of an infecting virus is significantly different both in the presence and in the absence of a potent immune response. It is the strong immunological response of the host, rather than any special properties of the virus, that accounts for the dynamic nature of HIV-1 replication, and it is this rapid replication, in response to immunological pressure, that accounts for the rapid emergence of variants (for more details, see Chapter 11.

Because variation is random, if the virus replicates rapidly and there is a relatively large pool of virus, there will be in the viral population variants that are immunologically distinct from a potential vaccine strain, as well as variants that are resistant to a given antiviral agent. For instance, HIV-1 variants that are resistant to nucleoside analogs and nonnucleoside inhibitors can be selected in vitro by passage of virus in the presence of the drugs, and such variants have also been detected in HIV-infected individuals taking such drugs therapeutically. Likewise, the extensive heterogeneity of the Env (surface [SU]) protein in field isolates of HIV and equine infectious anemia virus (EIAV) is at least partly due to selection for variants resistant to neutralizing antibodies. Indeed, it has been shown that in vitro passage of HIV-1 in the presence of a neutralizing monoclonal antibody directed against the SU protein leads to the rapid development of escape mutants that are resistant to the antibody (Yoshiyama et al. 1994).

Another potential difficulty is that retroviruses can establish persistent nonlytic or latent infection in an infected individual. Although the importance of latently or persistently infected cells to pathogenicity is still unclear, elimination of all of the latently infected cells either by vaccines or by antiretroviral drugs would be extremely difficult. Moreover, reactivation of viral expression from latently infected cells could potentially occur at any time. Management of retroviral infection in infected individuals is likely to require lifelong treatment.

It is also important to note that, in general, antiviral compounds (or antibiotics, for that matter) rarely eliminate a pathogen from an infected individual. Rather, they reduce the infection to a level where it can be controlled or eliminated by the immune system. However, if the immune system is impaired, as is the case for individuals with late-stage AIDS, then antiviral compounds are likely to be less effective.

As mentioned above, the pressing nature of the AIDS epidemic has fueled extensive research and development of antiretroviral drugs and vaccines. Although completely successful drug therapies and vaccines have not yet been developed, significant progress has been made. Moreover, the search for more effective antiretroviral drugs and vaccines has provided information that should be useful in the development of management of other viral infections.

Copyright © 1997, Cold Spring Harbor Laboratory Press.
Bookshelf ID: NBK19426PMID: 21433345


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