Lineage tracing reveals extensive compartmental dissemination and intra-clonal maturation of HIV Env vaccine-induced B cell responses

Induction of cross-neutralizing antibodies (Abs) against HIV-1 remains a high priority objective. Recent studies have demonstrated the induction of strain-restricted tier 2 neutralizing Ab responses, but these usually display limited potency and consistency. To gain insight into the composition and dynamics of the response induced by well-ordered HIV-1 envelope glycoprotein (Env) NFL trimers in primates, we combined monoclonal Ab isolation and high throughput sequencing of Ab repertoires from multiple immune compartments. By tracing 274 clonal lineages, we observed broad dissemination and highly dynamic intra-clonal evolution of the Env-specific response following boosting. Functional studies revealed that a single boost converted a non-neutralizing germline Ab to a potent tier 2 neutralizing Ab. This lineage was poorly expanded but the variants that persisted displayed increasing levels of somatic hypermutation (SHM) and improved functional properties with boosting, demonstrating the role of the Ab affinity maturation process also for apparently sub-dominant B cell clones.