DEVELOPMENT OF T-CELL INDEPENDENT VACCINES FOR HIV-1 AND OTHER INFECTIOUS AGENTS

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Infection with HIV-1 is characterized by a decrease on function and number of CD4+ T cells which are required for helper function in the antibody response to protein antigens. We have previously shown that antibody responses to HIV-1 proteins in mice are T-helper cell dependent, whereas HIV proteins and peptides, conjugated to Brucella abortus (BA) do not require CD4+ T cells. Subsequently, we conjugated an 18 amino acid peptide (N3V3) derived from the third variable region of HIV-MN envelope, containing both B and CTL epitopes, to BA (N3V3-BA) and to keyhole limpet hemocyanin (N3V3-KLH). Both conjugates were immunogenic in normal mice. IgG1 was the predominant isotype induced by V3-KLH, whereas IgG2a was the preeminent IgG subclass elicited by N3V3-BA. CTL were also elicited, by either construct, which could lyse peptide-pulsed and HIV-1-infected target cells in an MHC class I restricted manner. Since BA, as a carrier, can induce antibodies in mice depleted of CD4+ T cells and since BA can induce cytokines from CD8+ T cells, we investigated whether CTL and antibodies could be induced in mice lacking CD4+ T cells. N3V3-BA, but not N3V3-KLH, evoked both antibody and CTL responses in mice depleted of CD4+ T cells. In addition, sera from the mice immunized with the N3V3-conjugates were tested for ability to neutralize different HIV-1 isolates. Isolates which retain the G-P-G-R-A-F, namely, IIIB, MN and SF2 were neutralized (>50% syncytia inhibition) by sera from N3V3-BA immunized mice at titers of 160 or greater. The RF isolate, however, which is different at this site (G-P-G-R-V-I) was neutralized at a lower titer. These results indicate that B. abortus can be used as a carrier in the development of subunit vaccines designed to generate anti-HIV antibody and CTL responses in individuals with impaired CD4+ T cell function.