EXCEED THE SPACE PROVIDED. The overall goal of this proposal is to produce and characterize human monoclonal antibodies (HMAbs) that bind HIV-1 envelope glycoproteins and neutralize primary isolates. HMAbs will be generated from a unique cohort of HIVinfected patients who have been treated with HAART during acute HIV infection and who subsequently have demonstrated remarkable control of their viremia and manifest vigorous T cell responsesto HIV. A subset of patients have been through supervised treatment interruptions during which viremia rebounded transiently but was brought under control without resumption of therapy, presumbably as a result of a boost in functional virus specific T cellresponses. Our preliminary data has demonstrated that the peripheral blood of two acutely treated patients of this cohort provided an abundant source of B cells for generating HMAbs to CD4 induced epitopes. We will test the possibility that restimulation of immunity during treatment interruptions will increase the numbers of circulation env-specific B cells, enabling us to further probe the spectrum of env-specific B cell responses at the level of HMAb production. We have developed antibody screening methods which efficiently detect antibodies to envelope glycoproteins from primary isolates. We will investigate the time course for development of antibody responses to CD4i epitopes and will determine to what extent CD4i HMAbs manifest potent HIV-1 neutralizing activity. In addition, a major effort will be directed toward producing HMAbs reacting with oligomeric envelope glycoproteins of primary viruses, since certain neutralization epitopes maybe preferentially or uniquely exposed on oligomeric envelope on infectious virions. This type of antibody might be missed if we rely solely on assays utilizing solublized monomeric glycoproteins. Wewill test all monoclonal antibodies that we isolate for virus neutralization and characterize their epitopes. PERFORMANCE SITE ========================================Section End===========================================
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