A major goal of biomedical research is development of a vaccine that will lower significantly the rate of new infections of human immunodeficiency viruses (HIV), not only in this country, but worldwide. While positive results have come from both non-human primate and human Phase I and II trials, there have been obvious failures in both cases, emphasizing the need for novel vaccine strategies. Based on the hypothesis that the most effective vaccine against HIV infection and disease will be one that elicits not only mucosal and systemic but also humoral and cell-mediated immune responses that are broadly cross-reactive, two animal models will be used to test novel vaccines and assess cross-reactive immunity against HIV-1 strains from the same or different clades. First, the SHIV-macaque model will be used to characterize systemic and mucosal immune responses elicited by chimeric SIV/HIV virus-like particles and poliovirus replicons or naked DNA vaccines expressing SIV and HIV antigens. Furthermore, attempts will be made to enhance these responses by co-administering genes encoding various cytokines with candidate vaccines. Immune responses to be evaluated include inductions of antibodies in blood and mucosal secretions, neutralizing antibody activity, proliferative responses to immunogens, and cytotoxic T lymphocyte activity. Efficacy will be assessed by challenging immunized macaques either intravenously or vaginally with pathogenic SHIV-89.6P; these animals will then be monitored for evidence of infection. Second, chimpanzees infected with HIV-1 strains from clades B, D, or E will be exposed to unrelated strains, and both qualitative and quantitative changes in ongoing humoral and cellular immune responses will be determined. Whether super-infection occurs will be evaluated by PCR amplification of proviral DNA, heteroduplex assays, and DNA sequence analysis. In addition, disease course in naive chimpanzees inoculated by intravenous, cervical or rectal routes with a pathogenetic HIV-1 will be characterized and compared to that in HIV-1 infected chimpanzees which might become super-infected after inoculation with this strain. These studies will provide information on the feasibility of using poliovirus replicons and DNA vaccines to elicit protective immune responses, whether specific cytokines can enhance or alter the types of immunity elicited, and whether exposure of chimpanzees to multiple HIV-1 strains succeeds in broadening cross-reactivity such that infection or disease is prevented.
