G-112 HIV Env vaccine-elicited B cell responses against the virus primary receptor binding site

Abstract

Due to the high level of structural variability of HIV-1 Env, elicitation of neutralizing antibody responses to conserved neutralizing determinants such as the primary receptor binding site (CD4bs) is a major focus of HIV-1 vaccine development. Accordingly, a detailed understanding of how trimeric Env-elicited antibody responses evolve may help to achieve this goal. We interrogated the Ab repertoires from 2 rhesus macaques following a total of 5 inoculations with trimeric Env/adjuvant by antigen/epitope-specific single B cell analysis. We observe that the affinity maturation of CD4bs-specific Ig repertoire progressively occurs during the immunization course evidenced by the higher level of somatic hypermutation (SHM) following the 5th immunization than the 2nd immunization, which is associated with increasing Env binding affinity and virus neutralization potency. Furthermore, a notable portion of the CD4bs-specific Ig repertoire following the 2nd immunization is maintained following the 5th immunization, suggesting that clonal lineage persistence is achievable by Env protein vaccination. Interestingly, we find that the predominant and persistent CD4bs-specific Ab clonal lineages are expanded with larger population sizes and higher degrees of Env-binding affinity than the rest of the repertoire, which implies that antibody maturation and lineage expansion is mainly driven by antigen affinity selection. It is surprising that SHM accumulated particularly within the heavy chain framework 3, is associated with the affinity maturation of the dominant persistent clonal lineage. Our data provide an improved understanding of the dynamically evolving CD4bs-specific B cell response following Env immunization.