Pre-existing resistance in the latent reservoir can compromise VRC01 therapy during chronic HIV-1 infection

Abstract

Passive immunization with broadly neutralizing antibodies (bNAbs) of HIV-1 appears a promising strategy for eliciting long-term HIV-1 remission. When administered concomitantly with the cessation of antiretroviral therapy (ART) to patients with established viremic control, bNAb therapy is expected to prolong remission. Surprisingly, in clinical trials on chronic HIV-1 patients, the bNAb VRC01 failed to prolong remission substantially. Identifying the cause of this failure is important for improving VRC01-based therapies and unraveling potential vulnerabilities of other bNAbs. In the trials, viremia resurged rapidly in most patients despite suppressive VRC01 concentrations in circulation, suggesting that VRC01 resistance was the likely cause of failure. ART swiftly halts viral replication, precluding the development of resistance during ART. If resistance were to emerge post ART, virological breakthrough would have taken longer than without VRC01 therapy. We hypothesized therefore that VRC01-resistant strains must have been formed before ART initiation, survived ART in latently infected cells, and been activated during VRC01 therapy, causing treatment failure. Current assays preclude testing this hypothesis experimentally. We developed a mathematical model based on the hypothesis and challenged it with available clinical data. The model integrated within-host HIV-1 evolution, stochastic latency reactivation, and viral dynamics with multiple-dose VRC01 pharmacokinetics. The model predicted that single but not higher VRC01-resistant mutants would pre-exist in the latent reservoir. We constructed a virtual patient population that parsimoniously recapitulated inter-patient variations. Model predictions with this population quantitatively captured data of VRC01 failure from clinical trials, presenting strong evidence supporting the hypothesis. We attributed VRC01 failure to single-mutant VRC01-resistant proviruses in the latent reservoir triggering viral recrudescence, particularly when VRC01 was at trough levels. Pre-existing resistant proviruses in the latent reservoir may similarly compromise other bNAbs. Our study provides a framework for designing bNAb-based therapeutic protocols that would avert such failure and maximize HIV-1 remission.

Author summary

Antiretroviral therapy (ART) can control but not eradicate HIV-1. Stopping ART leads to rapid viral resurgence and progressive disease. ART is therefore administered lifelong. Tremendous efforts are ongoing to devise strategies that will enable stopping ART and yet prevent viral resurgence. One such strategy involves the administration of broadly neutralizing antibodies (bNAbs) of HIV-1 at the time of stopping ART. This strategy is expected to delay if not prevent viral resurgence. Surprisingly, treatment with VRC01, a potent bNAb, resulted in hardly any improvement in viral remission. In this study, we elucidate the cause of this failure. We hypothesized that VRC01-resistant strains may pre-exist in latently infected cells, which are unaffected by ART. They can thus outlast ART and get reactivated, triggering VRC01 failure. We built a detailed mathematical model based on this hypothesis and showed that it quantitatively captured observations of VRC01 failure in clinical trials on chronic HIV-1 patients. Our study thus identifies a potential vulnerability of bNAbs, namely, bNAb-resistant strains pre-existing in latently infected cells. Our model offers a framework for predicting bNAb-based treatment protocols that would preclude failure due to pre-existing resistance and maximally prolong remission.