Longitudinal analysis of antibody responses to HIV-1:mapping function to genotype

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DESCRIPTION (provided by applicant): To date no vaccination strategy against Human Immunodeficiency Virus (HIV) has been widely successful. HIV has developed mechanisms to escape the humoral response through a high mutation rate. In a subset of HIV-1 infected individuals, broadly neutralizing antibodies (bNAbs) have developed. These potent antibodies target preserved epitopes on the viral envelope across multiple clades. A viable vaccination strategy likely necessitates determining the mechanisms by which bNAbs evolve upon exposure to immunogens. The following two questions are addressed in this proposal: 1) How does the antibody repertoire evolve in HIV-1 infected individuals over time? 2) How does the functional antibody response to HIV-1 correlate to evolutionary stage? These questions will be addressed in Aim 1) which proposes to deep sequence longitudinal B-cell repertoires from HIV-1 infected individuals, using the sequences to assemble a phylogenetic tree depicting the divergent evolution of the antibody repertoires in individuals with broadly versus poorly neutralizing activity. Aim 2) proposes to perform a functional antibody phenotype screen of single B-cells from the same repertoires deep sequenced in Aim 1. The functional phenotype information will be linked to the phylogenetic map to identify bNAbs and their clonal ancestors. This will provide insight into the mechanisms of how bNAbs naturally evolve. Our results will contribute to the development of HIV-1 vaccination strategies by providing a blueprint for the elicitation of bNAbs.