Optimizing Humoral Responses to HIV-1 Env Vaccine Antigens

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Project Summary BCR affinity drives selection of mutations that increase potency and breadth in serum antibody (Ab), but also predisposes the fate choices of GC B cells towards terminal PC differentiation. We will study the role of BCR affinity in determining the fates of B cells exposed to serial immunizations or chronic SHIV infection to optimize vaccine efficacy. Parallel studies carried out in knock-in mice expressing the germline ancestor (UCA) of a V3 glycan bNAb lineage and in rhesus macaques (RMs) will merge lineage tracing of GC B and T cells with high throughput transcriptional analysis of individual lymphocytes to determine how and what immunological environments maximize the probability of eliciting broadly neutralizing antibody (bNAb) responses. We will use engineered Env vaccine antigens (Ags) to optimize the return of Bmem to secondary and tertiary GCs in BCR KI mice, and to determine how BCR affinity affects differentiation to the GC, Bmem and PC compartments. In SHIV infected RMs, we will in parallel map BCR affinities associated with nascent bNAb production and determine the effects of prior immunization with selected Env vaccines on subsequent, homologous or heterologous infection.