STUDY OF THE IMMUNOGENICITY OF DIFFERENT RECOMBINANT MENGO VIRUSES EXPRESSING HIV-1 AND SIV EPITOPES

Recombinant Mengo viruses expressing heterologous genes have proven to be safe and immunogenic in both mice and primates, and to be able to induce both humoral and cellular immune responses (Altmeyer et al., 19 95, 1996). Several recombinant Mengo viruses expressing either a large region (aa 65-206) of the HIV1 nef gene product, or cytotoxic T lymph ocyte (CTL) epitopic regions from the SIV Gag (aa 182-190), Nef (aa 15 5-178) and Pol (aa 587-601) gene products were engineered. The heterol ogous antigens were expressed either as fusion proteins with the Mengo virus leader (L) protein, or in cleaved form through autocatalytic cl eavage by the foot-and-mouth disease virus 2A protein. Rhesus macaques and BALB/c mice inoculated with the Mengo virus SIV recombinants fail ed to develop CTL responses against the SIV gene products, while one o f the HIV-Nef recombinants induced a weak CTL response in mice directe d to an HIV1 Nef peptide spanning positions 182-198. In contrast, BALB /c mice immunized with vaccinia virus recombinants expressing HIV1 Nef developed a strong CTL response to the 182-198 peptide and also respo nded to a second peptide spanning positions 73-81. These results indic ate that Mengo virus recombinants expressing HIV1 Nef and SIV CTL epit opes are weak immunogens. One of the fusion recombinants expressing SI V CTL epitopes failed to infect macaques even when used at high doses, while the recombinant expressing HIV1 Nef as a fusion protein failed to infect BALB/c mice. These results demonstrate that the expression o f certain heterologous sequences as fusion proteins with L can result in the loss of the ability of the recombinant to infect normally susce ptible animals.