The goal of an effective, safe vaccine against HIV-1 has not yet been realized. Although promising concepts have been tested and considerable understanding of HIV-1 immunobiology gained, effective prophylaxis of HIV-1 infection and AIDS remains elusive. In this R21 application, we propose to test a novel gene delivery vehicle, recombinant simian virus-40 (rSV40), as a vehicle to deliver HIV-1 and SIV gp120 envelope glycoproteins. rSV40 has several potential strengths as a vector for this type of immunization. It infects most cell types, is stable in lyophilized form, even at room temperature, and can be made at very high titer. As well, rSV40 does not elicit any detectable neutralizing antibodies, and so may be given multiple times, to boost or enhance immune responses against (e.g.) weakly immunogenic transgenes. We hypothesize that rSV40 carrying lentivirus gp120 can elicit both substantial antibody and cytotoxic T lymphocyte (CTL) responses against gp120. We have constructed a rSV40 that carries the HIV- INL4-3 gp120 gene (SVgp120) and expresses gp120. BALB/c mice inoculated multiply with SVgpl20 produce substantial antibody against gp120 by the second inoculation. In this application, we propose a collaborative project between Jefferson Medical College and the New England Regional Primate Research Center to test the ability of rSV40 to elicit immune responses vs. gpl20, and to evaluate protection from challenge with SIV. Thus, we will inoculate BALB/c mice with SVgpl20 monthly, with or without priming using vaccinia virus carrying NL4-3 env. Neutralizing and binding antibodies and CTL to gpl20 will be measured. The most effective immunization regimen will then be tested in rhesus macaque monkeys. We will make a rSV40 with SIVmac239 gp130 (SVgpl30). Applying the SVgpl20 immunization data, we will inoculate BALB/c with SVgpl30, measuring antibody and CTL to SIVmac239 gpl30, then repeat these studies in rhesus macaque monkeys. Immunized monkeys will then be challenged with pathogenic SIVmac239 and evaluated for disease progression. This approach will test the principle that multiple inoculations with a rSV40 vector bearing lentiviral gpl20 can enhance humoral and cellular immunity to these weak antigens, and afford protection from immunosuppressive lentivirus infection.
