A favorable follicular helper CD4+ T cell programming characterizes neutralization activity in chronic HIV infection.

A subset of people living with HIV (PLWH) can produce broadly neutralizing antibodies (bNAbs) against HIV, but the lymph node (LN) dynamics that promote the generation of these Abs are poorly understood. Here, we explored LN-associated histological, immunological, and virological determinants of bNAb generation in a cohort of antiretroviral therapy-naive PLWH. We found that participants who produce bNAbs, termed "neutralizers" (Ns), have a better-preserved LN-associated B cell follicle architecture than do PLWH who do not. The former was associated with a substantially higher in situ prevalence of B-cell lymphoma 6 (Bcl-6hi) follicular helper CD4+ T cells (Tfh), expressing a molecular program that favors their differentiation and stemness, and substantially reduced IL-10 follicular suppressor CD4+ T cells. Furthermore, our data reveal possible molecular targets mediating Tfh-B cell interactions in Ns. Together, we identify germinal center cellular and molecular signatures that could contribute to the development of bNAbs in PLWH.