Abstract

Design of a synthetic vaccine for HIV requires basic knowledge of the structure of helper and cytotoxic T-cell epitopes and neutralizing antibody epitopes, of ways to couple these to produce an effective immunogen, and of the role of viral sequence variation on MHC presentation of antigen. T-cell recognition, and cross-reactivity. We have been addressing all these issues for the HIV envelope and more recently also for the reverse transcriptase. We have now identified antigenic sites or epitopes from HIV envelope and reverse transcriptase recognized by cytotoxic T cells from both mice and humans in association with murine class I H-2 and human class I HLA antigens, as well as epitopes recognized by helper T cells in association with class II MHC molecules from both mice and humans. We have identified residues affecting interaction of peptides with MHC molecules and T-cell receptors and have examined the role of viral variability on presentation of these peptides by MHC molecules and recognition by T cells. One CTL epitope peptide was found to be presented by class II MHC molecules as well as class I MHC molecules and to be able to elicit CD4+ helper cells to aid in the induction of CD8+ CTL against the same peptide. One of the helper epitope peptides has been shown to be a powerful carrier for inducing neutralizing antibodies, and we have shown in rhesus monkeys that some of these helper peptides are immunogenic in primates and can elicit helper T cells that greatly augment the antibody response to a challenge in vivo with a suboptimal dose of HIV envelope protein compared to monkeys not given peptides, as one would want a vaccine to do. We have also identified multideterminant regions of the HIV-1 envelope and have made peptides corresponding to these that elicit helper T-cell responses in a large fraction of mouse strains and of outbred humans, as an approach to overcoming the problem of genetic restriction of T-cell responses. We have also developed a way of using purified recombinant proteins to elicit cytotoxic T cells in vivo by immunizing with the proteins incorporated into ISCOMs, and this method could be applied to an artificial vaccine as well. Some of these peptides should be candidates for immunotherapy trials in HIV-infected humans, as well as for vaccine development and diagnostic use.