Viral rebound kinetics following single and combination immunotherapy for HIV/SIV

HIV infection can be treated but not cured with antiretroviral therapy, motivating the development of new therapies that instead target host immune responses. Three such immunotherapies were recently tested in non-human primates - a TLR7-agonist, therapeutic vaccine, and broadly-neutralizing antibody - and cured a subset of animals by preventing or controlling viral rebound after antiretrovirals were stopped. However, their mechanism of action remains unknown; for example, whether they reduced the pool of latently-infected cells versus boosted antiviral immunity, and whether they acted independently or synergistically. Here we conduct a detailed analysis of the kinetics of viral rebound after immunotherapy, and use mathematical models combined with rigorous statistical fitting to quantify the impact of these interventions on viral dynamics. We find that the vaccine reduced reactivation of latent virus by 4-fold, and boosted the avidity of antiviral immune responses by 17-fold when alone and 210-fold when combined with the TLR7-agonist. In the context of later initiation of antiretroviral therapy only, the TLR7-agonist reduced latent reservoir reactivation by 8-fold, but also slightly increased target cell availability (1.5-fold). The antibody boosted immune response avidity (8-fold) and displayed no detectable synergy with the TLR7-agonist. To predict the impact of these immunotherapies in clinical trials, we calibrated a model of HIV rebound to human treatment interruption trials and simulated the effect of adding each therapy. Overall, our results provide a framework for understanding the relative contributions of different mechanisms of preventing viral rebound and highlight the multifaceted roles of TLR7-agonists for HIV/SIV cure.