DEVELOPMENT OF T-INDEPENDENT VACCINES FOR HIV-1 INFECTION

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HIV-1 infection is associated with decreased T helper cell function, so that vaccines or immunotherapy designed to stimulate the immune system of persons harboring the AIDS virus need to circumvent the requirement for T helper cells. Our strategy to accomplish this has been to use immune carriers which are T-cell independent and are capable of inducing antibody responses in the relative absence of T cells. Heat inactivated Brucella abortus (BA), has been shown to behave as T-independent type 1 carrier in human and murine antibody responses. Thus, we showed that HIV 1 proteins conjugated to BA were capable of eliciting neutralizing anti-HIV antibodies in mice, even in the relative absence of T cells. Sine lipopolysaccharide (LPS) from other gram negative bacteria can stimulate B cells, we postulated that LPS from BA would have similar properties. We purified LPS from BA and first test it for toxicity. Compared to LPS from E. coli (EC) LPS from BA was 10,000 fold less potent in inducing fever in rabbits; 300 fold less potent in causing lethality in mice; and 300 fold and 1400 fold less potent in inducing 1L1B and TNFa, respectively, from human monocytes. These results suggested that LPS from BA was much less likely than LPS from EC, to induce endotoxic shock in humans. We then tested LPS from BA from immune carrier function in mice. TNP-LPS BA was able to induce anti-TNP antibody repsonses from BALB/c, athymic and CBA/N mice. Thus, LPS BA, like the bacterium from which it is derived, behaves as a T-indenpendent type 1 carrier and may be useful as a carrier for vaccines which could bypass the requirement for helper T cells in HIV-1 dervied peptides conugated to Brucella abortus for ability to induce anti-HIV-1 neutralizing antibodies in mice and in the SCID-human model.