Our research is focused on primate immunodeficiency virus pathogenesis and AIDS vaccine development. Using passive immunization with broadly neutralizing monoclonal anti-HIV-1 antibodies in primates that were challenged with chimeric simian-human immunodeficiency viruses (SHIVs) carrying HIV-1 envelope genes, we demonstrated that infection is completely preventable, even after virus exposure. We now seek to induce protective immunity with active vaccination. Our strategy is to induce humoral as well as cellular immunity using recombinant viral protein immunogens and/or vectors. To test vaccine efficacy, we have developed a set of novel, pathogenic challenge SHIVs that are uniquely CCR5 tropic and encode recently transmitted HIV-1 envelope genes isolated from African individuals with newly acquired HIV-1 clade C infection. Thus, we have generated biologically relevant tools to develop vaccines against HIV-1 clade C, the world's most prevalent HIV-1 subtype. Our bimodal vaccine strategy has achieved partial protection, including protection from viremia, in rhesus macaques against challenge with heterologous SHIVs that encode HIV-1 envelopes that are mismatched with regards to the immunogen. We are now developing immunogens designed to induce higher titers of neutralizing antibodies with increased breadth.
In another set of vaccine studies, we have developed a peptide-based approach that is applicable for all members of a genetically heterogeneous population. Our strategy obviates the need to know the dominant epitope(s) and the MHC class I alleles of the vaccine recipients; using overlapping synthetic peptides (OSP), we were able to induce CD4+ and CD8+ T-cell responses against viral and cellular targets in all outbred and inbred mice tested. In a murine model of breast cancer, targeting a cellular oncogene by an OSP vaccine yielded a highly significant survival benefit after tumor cell challenge with a dose of malignant cells that induced lethal pulmonary metastases within about two months in the control mice. Importantly, no side effects were noted in the vaccinated, protected mice after extended follow-up. Our OSP-vaccine strategy represents a promising new concept for the development of cancer vaccines.