Immune Control Of Viral Replication

Vaccination Is Not Immunization Vaccine Risks Exposed

Vaccines Have Serious Side Effects

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As described above, there is accumulating circumstantial evidence that host factors, specifically the cytotoxic T-lymphocyte (CTL) response to HIV, play a significant role in determining the extent of viral replication. The initial decline in plasma HIV RNA following acute infection coincides with the appearance of HIV-specific CTLs (and not neutralizing antibody) (96). There is evidence that a highly specific CTL response may induce selective pressure on the viral quasispecies early on in the course of infection but that viro-logic escape can occur later if viral variants evolve that no longer correspond with the predominant HIV-specific CTL population (97). The relative frequency of HIV-specific CTLs appears to be inversely proportional to the plasma viral load, in both recently infected individuals (27) and those with more established disease (26). In a simian model of AIDS, eliminating CD8+ lymphocytes from monkeys with chronic SIV infection resulted in marked increases in plasma viral load (29). When SIV-specific CD8+ cells reappeared, viral replication was again suppressed. These observations led to a hypothesis that the viral load set point, the plasma HIV RNA steady state achieved when the rate of viral replication is held at a relatively constant level by host factors controlling replication, is determined primarily by the degree of antigen-driven CTL activity (31).

If the viral load set point is primarily determined by the extent of antigen-driven host immune responses, this phenomenon may help to explain the complex nature of latent HIV infection. Latently infected cells are established very early in the process of HIV infection, at a time when the HIV-specific cellular immune response has not fully matured. High levels of viral antigen ultimately stimulate a viral-specific CTL response, which coincides with the substantial decrease in plasma viral load that accompanies the resolution of the acute infection syndrome (96). Most patients who never receive potent antiretroviral therapy eventually succumb to progressive disease and are not able to control viral replication in the long term. However, exceptional individuals who have long-term nonprogression of HIV disease, as already described, appear to maintain some degree of HIV-specific CD4+ (98) and CD8+ T-cell responses (21) over extended periods. Because T-helper (CD4 + ) function is necessary for a fully effective CTL (CD8+) response, these two cellular responses are interdependent. Once patients are treated with potent antiretroviral therapy, however, viral antigen may eventually fall below the threshold necessary to maintain adequate CTL responses. A patient with acute symptomatic HIV infection prior to seroconversion, for example, developed HIV-specific CTLs that were attenuated as HAART was administered. When the patient abruptly discontinued therapy, a high plasma viral load and severe symptoms returned, followed by the reappearance of HIV-specific CTLs (99). If indeed the limited duration of HIV-specific CTL activity in most treated patients is caused by the lack of sustained, antigen-driven CTL responses, then a reappraisal of the therapeutic vaccination strategy is indicated. Once an individual has successfully achieved potent suppression of viral replication and an increase in general immune responsiveness (owing in part to a change in the cytokine milieu and lymphocyte redistribution) on HAART, restim-ulating HIV-specific CD4 and CD8 T cell immunity may be critical for achieving prolonged immunologic containment of viral replication.

The most promising strategy being explored for preventive HIV vaccines is to combine a prime immunogen (often incorporating HIV antigens within an attenuated viral vector) with boost peptide immunogens (gp120, gp160, or portions thereof) to induce CTL and neutralizing antibody, respectively (100,101). The ideal immunogen for therapeutic vaccination strategies, once chronic viral infection has already been established, may be an agent from the former category (designed to present antigens via a class I- or CTL-mediated mechanism rather than the more conventional aim of stimulating neutralizing antibody). Multicenter randomized clinical trials have been designed to evaluate the effects of combining HAART with HIV therapeutic vaccinations. One trial in development will compare the effects of different immune-based strategies (cycles of IL-2, a canarypox HIV immunogen, or both) in addition to HAART on the extent of virologic rebound when therapy is temporarily interrupted after 1 year.

Another intriguing line of evidence regarding the influence of host immune responses on the viral load set point derives from observations of intermittent therapy. Generally, adherence to combination drug regimens has been one of the tenets of HIV therapy, and there is evidence that incomplete suppression (such as with inappropriately low drug doses or frequently skipped doses) leads to a higher incidence of drug resistance over time. However, individual patients who intermittently received moderately potent but not complete suppression on the combination of didanosine and hydroxyurea, for example, appear to maintain HIV-specific CTL responses that correlate with strikingly delayed and attenuated viral rebound when treatment is held (102,103). Similarly, in studies of acutely infected patients who received antiretroviral therapy very early in the disease course, those patients who had abrupt, self-limited interruptions in HAART tended to develop strong HIV-specific CTL responses corresponding to very limited viral rebound on discontinuation of therapy (104). These anecdotal observations suggest the possibility that, under the right circumstances, strategic interruptions in therapy may result in restimulation of waning host immune responses that can mediate control of viral replication rates after therapy becomes intolerable or is no longer effective. Pilot studies are under way to determine the effects of different therapeutic strategies involving experimental vaccines and planned HAART interruptions as synergistic exogenous and endogenous immunizations, respectively.

Although complete viral eradication remains a worthy goal of HIV treatment, these preliminary observations and studies suggest that long-term immunologic control over HIV replication may be more eminently achievable and just as beneficial in the long run. Analogous to other common human viral pathogens (cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, and so on) that maintain some form of clinical latency following a temporary or subclinical illness, it is conceivable that immune-based therapies can induce a life-long truce with HIV that falls short of a complete cure. Avoidance of damaging high levels of viral replication without the need for costly and complex ongoing therapies would result in a dramatic change in the natural history of HIV infection for each infected individual and could potentially alter our perspective on the overall AIDS epidemic.

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