Identifying Critical Stages in Vaccine Induced IHIV-I Immunity The emergence of neutralizing serum antibody responses only after cellular immune responses have suppressed HIV replication has led to doubts regarding the importance of humoral immunity in controlling HIV infections. Nonetheless, rare, broadly cross-reactive antibodies are capable of neutralizing multiple isolates of HIV-1 in vitro, and when passively administered can prevent experimental infections. Thus, efficacious humoral immune responses remain crucial to the development of protective HIV-1 vaccines. Why are such antibodies rarely produced by HIV-infected patients? Why are the neutralizing epitopes present on the HIV-1 envelope so poorly immunogenic? Several explanations for the remarkable scarcity of HIV-1 broadly reactive, neutralizing antibody have been offered including the complexity and genetic plasticity of the HIV envelope antigens, the shielding of crucial antigen sites by glycosylation, competitive suppression by non-neutralizing surface antigens, immunological tolerance, and insufficient diversity in the primary antibody repertoire. All of these hypotheses are plausible, but remarkably detailed in situ studies of primary immune responses to HIV-1 antigens have not been performed. We know that HIV-1 neutralizing epitopes are poorly immunogenic but we do not know why. We shall, therefore, carry out studies to identify any deficits in the humoral responses of mice immunized with HIV-1 vaccines by focusing on the characteristic patterns of cellular migration, interaction, proliferation, and differentiation necessary for robust and efficacious antibody production. Our studies will use histologic, flow cytometric and molecular genetic comparisons of responses to HIV-1 and control vaccines and will identify those differences that may account for the rarity of protective HIV-1 antibody.
The project will identify optimal HIV-1 vaccine candidates by determining which generate efficacious germinal center responses including robust hypermutation and class-switch recombination, clonal proliferation and selection, and establishment of long-lived memory compartments. These studies are fundamental to the rational development of protective HIV-1 vaccines.
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