Inhibitory potential of autologous neutralizing antibodies sets quantitative limits on the rebound-competent HIV-1 reservoir
Garcia, M. A.; Farrell-Sherman, A.; Zhuo, J.; Fray, E. J.; Zinsser, A. M.; Aydin, B.; Sowers, K.; Li, H.; Lopez, B. M.; Abeyta-Lopez, A.; Chu, T.; Lubbeck, D.; Chae, M.; Varriale, J.; Westfall, D. H.; Lai, J.; Hoh, R.; Dalhuisen, T.; Simonetti, F. R.; Peluso, M. J.; Deeks, S. G.; Siliciano, R. F.; Cohn, L. B.; Siliciano, J. D.
Show abstract
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.
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