Origin of rebound virus in chronically SIV-infected Rhesus monkeys following treatment discontinuation

Po-Ting Liu,Erica N Borducchi,Dan H Barouch,Gregory Chin,Elena Bekerman,Noe B Mercado,Esther A Bondzie,Abishek Chandrashekar,Joseph Hesselgesser,Romas Geleziunas,Jinyan Liu,Brandon F Keele,Michael Mish,Peter Abbink

doi:10.1038/s41467-020-19254-2

Abstract

Viral rebound following antiretroviral therapy (ART) discontinuation in HIV-1-infected individuals is believed to originate from a small pool of CD4+ T cells harboring replication-competent provirus. However, the origin and nature of the rebound virus has remained unclear. Recent studies have suggested that rebound virus does not originate directly from individual latent proviruses but rather from recombination events involving multiple proviruses. Here we evaluate the origin of rebound virus in 16 ART-suppressed, chronically SIV-infected rhesus monkeys following ART discontinuation. We sequence viral RNA and viral DNA in these animals prior to ART initiation, during ART suppression, and following viral rebound, and we compare rebound viral RNA after ART discontinuation with near full-length viral DNA from peripheral blood and lymph node mononuclear cells (PBMC and LNMC) during ART suppression. Sequences of initial rebound viruses closely match viral DNA sequences in PBMC and LNMC during ART suppression. Recombinant viruses are rare in the initial rebound virus populations but arise quickly within 2–4 weeks after viral rebound. These data suggest that intact proviral DNA in PBMC and LNMC during ART suppression is likely the direct origin of viral rebound in chronically SIV-infected rhesus monkeys following ART discontinuation.

Highlights

Viral rebound following antiretroviral therapy (ART) discontinuation in HIV-1-infected individuals is believed to originate from a small pool of CD4+ T cells harboring replicationcompetent provirus
RT leads to durable suppression of HIV-1 replication in the majority of individuals, but the persistent viral reservoir in resting memory CD4+ T cells is the key barrier to HIV-1 cure and leads to viral rebound in the vast majority of HIV-1-infected individuals following ART discontinuation[1,2,3,4,5,6]
Prior studies from clinical trials of HIV-1-specific broadly neutralizing antibodies in which individuals underwent analytical treatment interruption (ATI) reported that latent proviruses prior to ATI and rebound viruses following ATI share very limited overlapping env sequences, suggesting that rebound viruses are either not present or are rare in the viral reservoir[7,8,9,10]. These studies suggested that rebound viruses a represented recombinants of multiple latent proviruses found in the reservoir during ART suppression[7,8,9,10]. To evaluate this question in further detail, we generate near full-length sequences of putative replication-competent viral DNA in PBMC and LNMC from ART-suppressed, SIV-infected rhesus monkeys, and we compare these sequences to rebound viral RNA sequences following ART discontinuation

Summary

Introduction

Viral rebound following antiretroviral therapy (ART) discontinuation in HIV-1-infected individuals is believed to originate from a small pool of CD4+ T cells harboring replicationcompetent provirus. To evaluate this question in further detail, we generate near full-length sequences of putative replication-competent viral DNA in PBMC and LNMC from ART-suppressed, SIV-infected rhesus monkeys, and we compare these sequences to rebound viral RNA sequences following ART discontinuation. Sequences from PBMC or LNMC during ART suppression, we isolated initial plasma rebound viruses in each monkey 1–4 weeks after ART discontinuation (Fig. 2), and env regions were sequenced.

Results

Conclusion