Immunotherapy for HIV Infection

Recent studies in persons with long-term non-progressing infection suggest that the immune response to HIV may be of sufficient magnitude, in rare cases, to successfully contain the virus and prevent the development of disease. This observation has led to more focused attempts to reconstitute effective immunity in infected persons. Encouraging data showing that potent antiviral therapy can augment production of naive CD4 cells, and may augment thymic function, provide further encouragement for these approaches.

A number of approaches for immune-based therapy are being investigated. Passive immunotherapy with immunoglobulins as well as HIV-1-specific gamma globulins and monoclonal antibodies may have direct antiviral effects, but efficacy may be limited because of lack of broad cross reactivity of antibody responses. Cytokines may serve to regulate immune responses as well as HIV-1 expression. Trials of intermittent IL-2 infusion are under way, as are trials of IL-12 therapy.

Some in vitro studies have shown that IL-12 can restore some HIV-1-specific cell-mediated immune responses. Adoptive cellular therapy with autologous cloned HIV-1-specific CTL as well as polyclonal populations of CD8 cells are under way, and although efficacy has not yet been determined, the early data indicate that this approach seems to be safe and that infused CTL home to infected cells.

Trials of adoptive therapy with autologous uninfected CD4 cells to correct the CD4 cell deficit are being planned.

Prospects for Vaccine Development

Ultimate global control of the HIV epidemic will likely require a vaccine that can elicit protective immunity. Although efforts to define the components of productive immunity in infected persons have been unsuccessful thus far, recent data from animal models of retrovirus infection indicate that a state of protective immunity may be an attainable goal. When immunized with an attenuated, nef-deleted SIV, rhesus macaques were found to be protected when subsequently challenged with wild-type pathogenic SIV. Not only were the animals protected from low-dose challenge, but they were also protected from high-dose challenge.

TABLE: - IMMUNE-BASED INTERVENTIONS FOR HIV INFECTION Passive immunity Immunoglobulins Monoclonal antibodies Thymic hormones Cytokine treatment Interleukin-2 Tumor necrosis factor Interferons Interleukin-12 Adoptive cellular therapy Therapeutic vaccination

Although the precise mechanism whereby these animals were protected has not been determined, these results indicate that protective immunity may be an achievable goal for HIV-1 infection.
Despite these promising results in the SIV model of HIV-1 infection, a number of potential obstacles exist to the development of an effective AIDS vaccine. Foremost among these is the genetic diversity of the viral genome. Most of this diversity occurs in the envelope gene, with as much as 20% divergence in nucleotide sequence among field isolates. Even within a single individual, multiple divergent strains of virus have been identified, reflecting an extremely high intrinsic mutation rate for the virus. The implications of such diversity for vaccine development are profound, because the virus acts as a moving target for any immune response that is generated.