Viral load-driven systemic immune exhaustion is an enabler of antibody breadth in HIV infection

A broadly neutralizing response to a human immunodeficiency virus (HIV) vaccine is a major goal of the field, yet the determinants of antibody breadth remain poorly defined. Antibody responses to HIV evolve over years of infection, developing unusual features such as high mutation rates in the subset of individuals that acquire breadth. Prior studies have established viral load as a key correlate of neutralization breadth; however, whether this reflects the failure of host immune control or virus-intrinsic features remains unclear. Using single-cell RNA sequencing, single-cell proteomics, and plasma neutralization assays in a longitudinal Kenyan cohort of women living with HIV prior to the availability of antiretroviral therapy, we identify systems-level immune correlates of antibody breadth. Broad and narrow neutralizers diverge early in infection along a viral load-driven axis with broad neutralizers exhibiting greater viral loads and CD4 T cell decline. Critically, across NK cells, CD8 T cells, and monocytes, broad neutralizers displayed greater magnitude of immune activation in early infection, followed by exhaustion in late infection, a functional decline that may dampen NK cell-mediated pruning of T follicular helper cells, creating a permissive environment for sustained germinal center activity and antibody maturation. Narrow neutralizers, by contrast, maintain functional cellular immunity but lack the antigenic pressure and permissive exhaustive state associated with breadth. These findings suggest a mechanistic framework in which viral load, cellular activation, and progressive immune exhaustion are multifactorial contributors to breadth. This has implications for immunogen design aimed at recapitulating breadth without exhaustion and cure strategies aimed at revitalizing the cellular immune response to HIV without undermining antibody responses. One Sentence SummaryIn a longitudinal cohort of ART-naive women living with HIV, immune profiling reveals that neutralization breadth is associated with viral load-driven early immune activation followed by exhaustion, with implications for immune function in therapeutic interventions like vaccination and cure in people living with HIV.