Inhibitory potential of autologous neutralizing antibodies sets quantitative limits on the rebound-competent HIV-1...

HIV-1 cure requires preventing viral rebound after treatment interruption, but quantitative criteria defining the rebound-competent reservoir are lacking. We studied individuals undergoing observational treatment interruption to identify virologic and immunologic determinants of rebound. In 9 of 13 participants, rebound viruses were genetically identical or similar to proviruses in circulating resting CD4⁺ T-cells. We found no evidence of recombination among rebound sequences, rather resistance to autologous neutralizing antibodies was a critical determinant of viral rebound. Using inhibitory potential ( IP ), the log reduction in single-round infection at physiologic IgG concentrations, we defined quantitative limits governing rebound-competency. Reservoir variants exhibited a wide range of IP values (0.4-8.2 logs), whereas rebound viruses were minimally inhibited (0.5-2.8 logs), indicating that inhibition by even up to 2.8 logs (631-fold) cannot prevent rebound. Longitudinal analyses revealed that waning aNAb potency allows previously neutralized variants to gain rebound potential. Thus, rebound competency is a dynamic, immune-governed property defined by quantitative immunologic constraints.