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Session 25 Oral Abstract Session Immunology Session Time: Wednesday, 10 am - 12:30 pm Room 6C

11:00   105. HIV-1 Core Envelope Glycoproteins Deficient in T-Cell Helper Epitopes C. Grundner*1, J. Kang1, M. Koch1, J. Sodroski1,2, and R. Wyatt3 1Dana-Farber Cancer Inst., Boston, MA; 2Harvard Med. Sch. and Harvard Sch. of Publ. Hlth., Boston, MA; and 3NIAID Vaccine Res. Ctr., NIH, Bethesda, MD Background: The development of an effective HIV-1 vaccine will likely need to efficiently elicit broadly-neutralizing antibodies directed against conserved receptor-binding regions of the HIV-1 gp120 envelope glycoprotein (Env). The generation of mature antibody responses requires the assistance of T-cell help from activated CD4+ helper T cells. Although gp120 elicits reasonable antibody responses in vivo, much of this response is directed against either variable envelope elements or non-neutralizing epitopes. We created gp120 V3+ core Env by deleting the variable loops V1 and V2 and parts of the N- and C-termini to eliminate many of these non-neutralizing determinants. We have evidence that suggests that these modified gp120 V3+ core Env derived from primary isolates are deficient in T cell helper epitopes. Methods: Recombinant gp120 core Env derived from a laboratory-adapted virus (HXBc2) and 2 primary viruses (YU2 and JR-FL) were produced with and without heterologous helper epitopes in insect cells. The proteins were inoculated into mice and outbred rabbits. Analysis of sera from animals immunized with core Env was performed by anti-gp120 ELISA. Results: When core Env was inoculated into 2 strains of mice, the primary isolate Env core was extremely poor in eliciting gp120-directed antibody responses, whereas the HXBc2 core Env elicited a significant antibody response. The addition of heterologous T cell helper epitopes restored the ability of the YU2 core Env to elicit high-titer, gp120-specific antibodies. A similar pattern was observed in outbred rabbits immunized with the YU2 Env. Conclusions: These data suggest that gp120 Env may be selected in vivo to limit T cell help. Although these results were observed in the context of both inbred and outbred non-human MHC, they raise the possibility that gp120 from primary HIV-1 isolates may have limited epitopes recognized by human MHC alleles. Viral evasion from recognition by CD4+ T helper cells might be another viral immune escape mechanism. Inclusion of heterologous helper sequences may be valuable to unmask the full immunological potential of HIV-1 subunit vaccine candidates.

©2002 9th Conference on Retroviruses and Opportunistic Infections