Modeling how early passive immunization with broadly neutralizing antibodies elicits lasting control of SHIV infection

Abstract

Antiretroviral therapy (ART) for HIV-1 infection is life-long. Stopping therapy typically leads to the reignition of infection and progressive disease. In a major breakthrough, recent studies have shown that early initiation of ART can lead to sustained post-treatment control of viremia, raising hopes of long-term HIV-1 remission. ART, however, elicits post-treatment control in a small fraction of individuals treated. Strikingly, passive immunization with broadly neutralizing antibodies (bNAbs) of HIV-1 early in infection was found recently to elicit long-term control in a majority of SHIV-infected macaques, suggesting that HIV-1 remission may be more widely achievable. The mechanisms underlying the control elicited by bNAb therapy, however, remain unclear. Untreated infection typically leads to progressive disease. We hypothesized that viremic control represents an alternative but rarely realized outcome of the infection and that early bNAb therapy triggers a dynamical switch to this outcome. To test this hypothesis, we constructed a model of viral dynamics with bNAb therapy and applied it to analyse clinical data. The model fit quantitatively the complex longitudinal viral load data from macaques that achieved lasting control. The model predicted, consistently with our hypothesis, that the underlying system exhibited bistability, indicating two potential outcomes of infection. The first had high viremia, weak cytotoxic effector responses, and high effector exhaustion, marking progressive disease. The second had low viremia, strong effector responses, and low effector exhaustion, indicating lasting viremic control. Further, model predictions suggest that early bNAb therapy elicited lasting control via pleiotropic effects. bNAb therapy lowers viremia, which would also limit immune exhaustion. Simultaneously, it can improve effector stimulation via cross-presentation. Consequently, viremia may resurge post-therapy, but would encounter a primed effector population and eventually get controlled. ART suppresses viremia but does not enhance effector stimulation, explaining its limited ability to elicit post-treatment control relative to bNAb therapy. Author SummaryIn a remarkable advance in HIV cure research, a recent study showed that 3 weekly doses of HIV-1 broadly neutralizing antibodies (bNAbs) soon after infection kept viral levels controlled for years in most macaques treated. If translated to humans, this bNAb therapy may elicit a functional cure, or long-term remission, of HIV-1 infection, eliminating the need for life-long antiretroviral therapy (ART). How early bNAb therapy works remains unknown. Here, we elucidate the mechanism using mathematical modeling and analysis of in vivo data. We predict that early bNAb therapy suppresses viremia, which reduces exhaustion of cytotoxic effector cells, and enhances antigen uptake and effector stimulation. Collectively, these effects drive infection to lasting control. Model predictions based on these effects fit in vivo data quantitatively. ART controls viremia but does not improve effector stimulation, explaining its weaker ability to induce lasting control post-treatment. Our findings may help improve strategies for achieving functional cure of HIV-1 infection.