Speaker
Description
Recent studies have shown that the administration of combinations of latency reversal agents (LRAs) and broadly neutralizing antibodies (bNAbs) at the time of antiretroviral therapy (ART) cessation significantly enhances the chances of eliciting long-term control of HIV post treatment over that with ART alone. Surprisingly, neither LRAs nor bNAbs succeed independently, implying strong synergy between them. The mechanism(s) underlying the synergy remain unknown, precluding optimal deployment of the drug combinations. Here, we posit a mechanism of synergy and evaluate it using mathematical modeling. When ART is successful, productive viral replication is nearly completely halted. Under these circumstances, LRAs reactivate latently infected cells, triggering bursts of viral production. bNAbs bind to these virions and enhance antigen presentation to immune cells, stimulating HIV-specific CD8 T-cells. The combination, administered towards the end of ART, thus leaves a reduced latent reservoir and a primed CD8 T-cell population. The smaller reservoir size suppresses the magnitude of the viral rebound post ART. The primed CD8 T-cell population proves adequate to exert lasting control of the rebounding virus. Our model, based on the above mechanism of synergy, recapitulated clinical data of long-term remission following the LRA/bNAb combination therapy. The model offered insights into the role of CD8 T-cells in eliciting and maintaining viremic control and presented a route to identifying optimal dosages of LRAs and bNAbs for achieving this control, informing ongoing clinical trials.
