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bioRxiv · 10.1101/2020.02.14.940395

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

Saha, A.·Dixit, N. M.
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Abstract

Broadly 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.

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Saha, A., Dixit, N. M.. 2020-02-15. Pre-existing resistant proviruses can compromise maintenance of remission by VRC01 in chronic HIV-1 infection. https://doi.org/10.1101/2020.02.14.940395

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