The success of vaccination against HIV- 1 may depend on the ability to induce in humans effective B cell and CTL responses against the virus. As a first step, it is proposed to develop in animals effective immunization protocols involving the use of recombinant influenza and vaccinia viruses. Earlier, it was shown that influenza viruses expressing foreign B cell epitopes can induce in mice a long-lasting systemic and mucosal immune response against these epitopes. In addition, immunization of mice with influenza viruses expressing foreign CTL epitopes, followed by appropriate vaccinia virus recombinants, was shown to induce a vigorous and unprecedented CTL response. The present application aims to develop influenza and vaccinia virus recombinants expressing HIV- and SIV-specific sequences in order to induce high-titered specific B and CTL responses in mice. In addition, it is planned to use these viral vectors to characterize the immune responses in pigtailed and rhesus macaques and to take advantage of an SHIV and SIV challenge system in pigtailed macaques. It is hoped that information obtained using influenza virus and vaccinia virus recombinants in mice and in the monkey model will ultimately help in developing protective and safe HIV vaccines for humans.
In Specific Aim 1, the applicants propose to construct influenza virus vectors expressing an HIV gp160 epitope, known to be recognized by human cross-neutralizing antibodies, or the SIV gag protein which is known to contain CTL epitopes. The ability of these recombinant influenza and vaccinia virus vectors to induce antiviral humoral and cellular immune responses in mice will then be determined in Specific Aim 2. Studies will focus on the development of neutralizing activity against different HIV-1 isolates in a syncytium formation inhibition assay, and the development of CTL activity. Finally in Specific Aim 3, the applicants will characterize the immune response and levels of protection against retrovirus infection in primates vaccinated with recombinant influenza and vaccinia virus vectors expressing shared HIV and SIV antigens. This will involve adapting the viruses to primates. It is hoped that information obtained using influenza virus and vaccinia virus recombinants in mice and in the monkey model will ultimately help in developing protective and safe HIV vaccines for humans.
