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.

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.

Another obstacle to be overcome is the type specificity of immune responses generated to candidate vaccines, because immune responses generated by an immunogen representing a single field isolate are unlikely to cross react with all field isolates. In addition, although some of the protein-based HIV-1 vaccine candidates have induced reasonably strong neutralizing antibodies when tested against laboratory strains of virus, these antibodies have been much less effective in neutralizing field isolates of HIV-1.

Once candidate immunogens are identified, animal testing for efficacy would be ideal, but may be difficult for a number of reasons. Although chimpanzees become infected with HIV-1, they do not generally develop disease. Rhesus macaques develop an immunodeficiency disease similar to AIDS when infected with SIV, but cannot be infected with HIV, are expensive to maintain, and are in limited supply. The potential utility of immunodeficient mice reconstituted with human fetal tissues, providing them with a “human” immune system, remains to be demonstrated. The biggest obstacle will be demonstration of efficacy, which will require large field trials in a population showing a high enough incidence of new infection that statistically significant data can be generated in a reasonable period. Demonstration of efficacy in one population may not translate to other populations. For example, protection of persons infected by sexual exposure will not necessarily imply that such a vaccine would protect intravenous drug abusers as well, who may be exposed to a higher initial inoculum of virus. As with HIV-infected persons, the potential for discrimination against vaccines due to positive serology will have to be addressed.

Although these obstacles exist, a number of clinical trials are already under way with a variety of vaccine candidates. These include soluble Gag or envelope proteins; recombinant vaccine virus containing the HIV-1 envelope gene; pseudovirion vaccines that resemble whole HIV particles but are modified to exclude the viral genome or render it harmless; retroviral vectors; and whole killed virus vaccines. A number of these approaches also are being evaluated as potential therapeutic vaccines in an attempt to improve the host immune response to the virus.

Combinations of some of these approaches also are under investigation, and appear to be the most promising. In subjects immunized with vaccinia-HIV-1 GP 160, dramatic increases in HIV-1 envelope antibodies were observed when vaccinees were boosted with recombinant gp 160 protein. Other approaches in various stages of development include use of recombinant vaccinia viruses. Modified vaccinia Ankara (MVA) looks particularly immunogenic. Given the potential importance of inducing mucosal immune responses, there also is interest in attenuated salmonella-HIV recombinants, which may be more effective at inducing mucosal immunity.

References:
_{Autran B, Carcelain G, Li TS, et al: Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease [see comments]. Science 277:112-116, 1997. Treatment of persons with prolonged highly active antiretroviral therapy leads to the progressive generation of nai ve CD4 lymphocytes. The possibility that these cells might be reeducated offers hope for immunotherapy and immune reconstitution.}

Brodie SJ, Lewinsohn DA, Patterson BK, et al: In vivo migration and function of transferred HIV-1-specific cytotoxic T cells. Nature Medicine 5:34, 1999. This is the best demonstration that adoptively transferred CTL are able to home to sites of viral replication, indicating an antiviral role for these cells.

Douek DC, McFarland RD, Keiser PH, et al: Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690, 1998. This study shows that the thymus continues to remain functional well into adult life, and that thymic production of naive cells is increased in persons treated with highly active antiviral therapy.

Kahn JO, Walker BD: Acute human immunodeficiency virus type 1 infection. N Engl J Med 339:33-39, 1998. A review of HIV pathogenesis in the early stages of infection.

LaCasse RA, Follis KE, Trahey M, et al: Fusion-competent vaccines: Broad neutralization of primary isolates of HIV. Science 283:357-362, 1999. This study shows that broadly cross-reactive neutralizing antibodies can be generated with an immunogen consisting of the fusion complex of the envelope glycoprotein.

Letvin NL: Progress in the development of an HIV-1 vaccine. Science 280:1875-1880, 1998. An excellent review article regarding the current state of vaccine development for HIV, and the problems being encountered.

Ogg GS, Jin X, Bonhoeffer S, et al: Quantitation of HIV-1 specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279:2103-2106, 1998. This study demonstrates that there is a negative correlation between CTL and viral load in HIV infection, and introduces a novel technology that allows for direct visualization of CTL by flow cytometry.

Rosenberg ES, Billingsley JM, Caliendo AM, et al: Vigorous HIV-1-specific CD4+ T cell responses correlate with control of viremia. Science 278:1447, 1997. This study demonstrates that virus-specific T helper cells are a critical host defense mechanism, and that early treatment of acute HIV infection results in the generation of these responses.

Schmitz JE, Kuroda MJ, Santra S, et al: Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283:857-860, 1999. Depletion of Cd8 cells and CTL leads to a dramatic increase in viral load in an animal model of AIDS virus infection. These data indicate that CTL are critical to maintaining the viral set point in chronic infection.