The HIV-1 latent reservoir is largely sensitive to circulating T cells.

Joanna A Warren,David M Margolis,Joann D Kuruc,Nilu Goonetilleke,Zabrina L Brumme,Sarah Joseph,Nadia R Roan,Yinyan Xu,Julia M Sung,Ronald Swanstrom,Daniel R Macmillan,Nancie Archin,Matthew J Moeser,Shuntai Zhou,Jennifer Kirchherr,Adaora A Adimora,Olivia Council,Cynthia L Gay

doi:10.7554/elife.57246

Abstract

HIV-1-specific CD8+ T cells are an important component of HIV-1 curative strategies. Viral variants in the HIV-1 reservoir may limit the capacity of T cells to detect and clear virus-infected cells. We investigated the patterns of T cell escape variants in the replication-competent reservoir of 25 persons living with HIV-1 (PLWH) durably suppressed on antiretroviral therapy (ART). We identified all reactive T cell epitopes in the HIV-1 proteome for each participant and sequenced HIV-1 outgrowth viruses from resting CD4+ T cells. All non-synonymous mutations in reactive T cell epitopes were tested for their effect on the size of the T cell response, with a≥50% loss defined as an escape mutation. The majority (68%) of T cell epitopes harbored no detectable escape mutations. These findings suggest that circulating T cells in PLWH on ART could contribute to control of rebound and could be targeted for boosting in curative strategies.

Highlights

Antiretroviral therapy (ART) has transformed human immunodeficiency virus type 1 (HIV-1) from a fatal disease to a chronic condition
We have recently shown that HIV-1-specific T cell responses are detectable ex vivo and are highly stable in people living with HIV-1 (PLWH) on durable ART suppression (Xu et al, 2019), with others showing that ex vivo isolated CD8 + T cells can suppress HIV-1 superinfected CD4+ T cells as well as in vitro reactivated reservoir virus (Sung et al, 2015; Shan et al, 2012)
HIV-1-specific T cell responses and the size of the HIV-1 reservoir were measured in 25 PLWH durably suppressed by combination ART

Summary

Introduction

Antiretroviral therapy (ART) has transformed human immunodeficiency virus type 1 (HIV-1) from a fatal disease to a chronic condition. ART must be taken life-long as interruption of therapy in people living with HIV-1 (PLWH) mostly results in viral rebound within weeks (Davey et al, 1999; Crowell et al, 2019; Bar et al, 2016; Buzon et al, 2014). This rebound results from cells harboring HIV-1 DNA that is integrated into the host genome.

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