Beyond neutralization: Fc-mediated antibody functions in HIV reservoir control

PURPOSE OF REVIEW: Despite advances in antiretroviral therapy, HIV reservoirs remain a major barrier to cure. This review highlights recent advances in understanding how antibody Fc-mediated effector functions contribute to the clearance of HIV-infected cells and to immune modulation that may support durable viral control. RECENT FINDINGS: Successful antibody-mediated clearance of HIV-infected cells is dependent on efficient target cell recognition, overcoming viral immune-evasion mechanisms, and recruitment of functional innate effector cells. Recent approaches including CD4 mimetics, Fc glycoengineering, Fc amino acid modifications, and NK cell-directed strategies enhance antibody-dependent cellular cytotoxicity and phagocytosis of HIV-infected cells. Therapeutic vaccination and broadly neutralizing antibody (bNAb)-based interventions have renewed interest in antibody-mediated immune control, with vaccination inducing multifunctional Fc-mediated antibody responses and bNAbs delaying viral rebound in some individuals. SUMMARY: These advances highlight the potential of Fc-mediated antibody functions to complement HIV cure strategies by promoting HIV-infected cell clearance. Emerging evidence also supports a role for antibody-induced vaccinal effects in shaping immune responses associated with viral control. However, defining the mechanisms underlying these effects and their contribution to reservoir reduction remains an important priority for HIV cure research.