The functional antibody landscape in HIV post-treatment controllers is heterogeneous.

HIV-1 establishes a latent reservoir early in infection that persists during antiretroviral therapy (ART), typically leading to rapid viral rebound upon treatment interruption in most people living with HIV-1. However, a rare group known as post-treatment controllers (PTCs) can maintain low or undetectable viral loads for extended periods after ART cessation, offering critical insights into durable HIV remission. While immune responses are thought to play a key role in this control, the contribution of humoral immunity-particularly Fc-mediated antibody functions-remains insufficiently defined. In this study, we explored the influence of humoral responses on viral rebound in PTCs using a comprehensive systems serology approach. We profiled Env-specific antibody characteristics and Fc-effector functions-including antibody-dependent cellular phagocytosis, antibody-dependent neutrophil phagocytosis, antibody-dependent complement deposition, and antibody-dependent NK cell activation-in PTCs and matched non-controllers (NCs). Baseline antibody features prior to ART interruption did not clearly distinguish PTCs from NCs, and antibody responses evolved dynamically and in a highly individualized manner during viral rebound. Notably, distinct and individual-specific shifts in Fc-functional antibody signatures occurred during rebound, indicating that the humoral immune system actively adapts during this critical period. These findings highlight the complexity and adaptability of antibody-mediated responses, shaped by dynamic processes during rebound rather than static baseline features. This work underscores the value of longitudinal immune profiling to delineate how humoral immunity evolves in relation to, but not necessarily driving, post-treatment control.IMPORTANCEMost people living with HIV experience a quick return of the virus after stopping antiretroviral therapy (ART). However, a small group-post-treatment controllers (PTCs)-can keep the virus suppressed without ongoing treatment. This study examined whether antibody responses, especially those involving Fc-mediated functions, play a role in this control. This study compared antibody features and immune functions in PTCs and matched individuals who did not control the virus after stopping ART. They found that antibody profiles before treatment interruption did not predict who would control the virus. Instead, antibody responses changed over time in unique ways during viral rebound. These shifts suggest that the immune system adapts dynamically rather than relying on fixed traits. The findings highlight the importance of tracking immune changes over time to better understand how long-term HIV control may occur, even if antibodies alone may not be the driving force behind post-treatment remission.