Shreya Chowdhury

SYNERGISTIC EFFECT OF IMMUNE STIMULATION AND LATENCY REVERSAL MAY ELICIT LONG-TERM REMISSION OF SIV/SHIV INFECTION

Current antiretroviral therapies (ART) for HIV infection are not curative. Extensive efforts are ongoing to devise strategies for eliciting cure. Recently experimental studies observed that a combination of latency reversal agents (LRAs) and broadly neutralizing antibodies (bNAbs) induced long-term remission of HIV infection, although the drugs failed individually. A question of great current interest follows: Why does combination therapy succeed while individual drugs fail? We hypothesized that LRA-induced reactivation of latent cells during suppressive ART stimulates transient viremia and promotes immune-complex formation with passively administered bNAbs that leads to effector priming against the virus, resulting in viremic control post-ART interruption. We test this hypothesis by constructing a mathematical model incorporating the effects of interventions on host immune cells. Our model predictions explained numerous confounding experimental observations. Importantly, it explained how the combination treatment works by simultaneously targeting latently infected cells and stimulating immune responses while the individual drugs fail. Furthermore, we show how the framework could be used to predict treatment strategies that would improve the chances of achieving a cure for HIV, which future experiments would test