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

Abstract

16Broadly neutralizing antibodies (bNAbs) of HIV-1 hold promise of eliciting long-term HIV-1 17 remission. Surprisingly, the bNAb VRC01, when administered concomitantly with the cessation 18 of successful antiretroviral therapy (ART), failed rapidly in chronic HIV-1 patients. We 19 hypothesized that the failure was due to VRC01-resistant strains that were formed before ART 20 initiation, survived ART in latently infected cells, and were reactivated during VRC01 therapy. 21 Current assay limitations preclude testing this hypothesis experimentally. We developed a 22 mathematical model based on the hypothesis and challenged it with available clinical data. The 23 model integrated within-host HIV-1 evolution, stochastic latency reactivation and viral dynamics 24 with multiple dose VRC01 pharmacokinetics. With a virtual patient population, model predictions 25 quantitatively captured data from two independent clinical trials. Accordingly, we attributed 26 VRC01 failure to single-mutant VRC01-resistant proviruses in the latent reservoir triggering viral 27 recrudescence, particularly during trough VRC01 levels. Accounting for pre-existing resistance 28 may help bNAb therapies maximize HIV-1 remission. 29 30 Antiretroviral therapy (ART) for HIV-1 infection rapidly suppresses viremia to 32 undetectable levels and curtails disease progression but is unable to eradicate the virus. 1 33 Discontinuation of ART, even long after viremic control is established, typically leads to rapid 34 viral rebound, often within days to weeks of discontinuation, and to progressive disease. 2 The 35 rebound is caused by a reservoir of latently infected cells 3 that is formed soon after infection 4 . The 36 reservoir is sustained by cell proliferation 5,6 , which can continue even when ART has stopped new 37 infections, allowing the reservoir to exist long-term 7 . The reservoir can get reactivated 38 stochastically and reignite infection once ART is stopped 8,9 . ART must therefore be administered 39 lifelong. In a remarkable breakthrough, the VISCONTI study showed that when ART is 40 administered early in infection, some individuals can maintain viremic control for many years after 41 the cessation of ART 10 . This study has raised hopes of a functional cure, or long-term remission, 42 of HIV-1, where the viremic control once established by ART can be maintained without lifelong 43 treatment 11 . The success of ART in inducing post-treatment control, however, is small: only ~5-44 15% of the patients treated achieve lasting post-treatment control 12 . Enormous efforts are 45 underway to improve this success rate 11 . 46 One strategy that holds promise is to administer broadly neutralizing antibodies (bNAbs) 47 of HIV-1 for a short period post-ART, i.e., during an analytical treatment interruption (ATI) 13,14 . 48 bNAbs target diverse viral genomic variants 15,16 , and are expected to suppress viremia arising from 49 the reactivation of latently infected cells 17,18 . Simultaneously, they may engage the host immune 50 system 19 , ...