Efforts to broaden HIV-1-specific immunity by boosting with heterologous peptides or envelope protein and the influence of prior exposure to virus

In two previous studies, we have demonstrated the successful protection of human immunodeficiency virus type 1 (HIV-1)-vaccinated rhesus macaques from challenge with SHIVSF13 with envelop immunogens derived from the closely r elated HIV-1(SF2) strain. Here we report on two follow-up studies in which we aimed to broaden immunity in order to elicit protection from a more dive rse heterologous challenge with SHIVSF33. In the first study, animals were boosted once with HIV-1(SF33) V2 and V3 peptides that were cross-linked to influenza immune-stimulating complexes (ISCOMs). In the second study, monke ys were boosted twice at 12-week intervals, using a heterologous recombinan t gp120 derived from HIV-1(SF33) that was either incorporated into ISCOMs o r mixed with the MF59 adjuvant. In both studies, the animals were challenge d with 50 monkey infectious doses of SHIVSF33 4 weeks after the final boost . All controls became readily infected with the heterologous challenge viru s SHIVSF33. Neither boosting with heterologous SF33 peptides or gp120 affor ded protection from infection to SF2-vaccinated animals that had previously resisted SHIVSF13 challenge. These results demonstrate the importance of d eveloping vaccine strategies that are capable of generating broad immune re sponses early in the immunization protocol. Furthermore, these findings may illustrate the potential pitfalls of early antigenic sin.