Quality and quantity of TFH cells are critical for broad antibody development in SHIVAD8 infection

Broadly neutralizing antibodies (bNAbs) protect against HIV-1 infection, yet how they are generated during chronic infection remains unclear. It is known that T follicular helper (T-FH) cells are needed to promote affinitymaturation of B cells during an immune response; however, the role of T-FH during HIV-1 infection is undefined within lymph node germinal centers (GCs). We use nonhuman primates to investigate the relationship in the early stage of chronic SHIVAD8 (simian-humanimmunodeficiency virus AD8) infection between envelope (Env)-specific T-FH cells, Env-specific B cells, virus, and the generation of bNAbs during later infection. Wefound that both the frequency and quality of Envspecific T-FH cells were associated with an expansion of Env-specific immunoglobulin G-positive GC B cells and broader neutralization across HIV clades. We also found a correlation between breadth of neutralization and the degree of somatic hypermutation in Env-specific memory B cells. Finally, we observed high viral loads and greater diversity of Env sequences in rhesus macaques that developed cross-reactive neutralization as compared to those that did not. These studies highlight the importance of boosting high-quality T-FH populations as part of a robust vaccine regimen aimed at eliciting bNabs.