Pre-existing resistant proviruses can compromise maintenance of remission by VRC01 in chronic HIV-1 infection

Abstract

AbstractBroadly neutralizing antibodies (bNAbs) of HIV-1 hold promise of eliciting long-term HIV-1 remission. Surprisingly, the bNAb VRC01, when administered concomitantly with the cessation of successful antiretroviral therapy (ART), failed rapidly in chronic HIV-1 patients. We hypothesized that the failure was due to VRC01-resistant strains that were formed before ART initiation, survived ART in latently infected cells, and were reactivated during VRC01 therapy. Current assay limitations 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. With a virtual patient population, model predictions quantitatively captured data from two independent clinical trials. Accordingly, we attributed VRC01 failure to single-mutant VRC01-resistant proviruses in the latent reservoir triggering viral recrudescence, particularly during trough VRC01 levels. Accounting for pre-existing resistance may help bNAb therapies maximize HIV-1 remission.