Antigen-responsive CD4+ T cell clones contribute to the HIV-1 latent reservoir.

Pilar Mendoza,Michel C Nussenzweig,Victor Ramos,Lillian B Cohn,Thiago Y Oliveira,Christian Gaebler,Mila Jankovic,Julia R Jackson,Marina Caskey

doi:10.1084/jem.20200051

Abstract

Antiretroviral therapy suppresses but does not cure HIV-1 infection due to the existence of a long-lived reservoir of latently infected cells. The reservoir has an estimated half-life of 44 mo and is largely composed of clones of infected CD4+ T cells. The long half-life appears to result in part from expansion and contraction of infected CD4+ T cell clones. However, the mechanisms that govern this process are poorly understood. To determine whether the clones might result from and be maintained by exposure to antigen, we measured responses of reservoir cells to a small subset of antigens from viruses that produce chronic or recurrent infections. Despite the limited panel of test antigens, clones of antigen-responsive CD4+ T cells containing defective or intact latent proviruses were found in seven of eight individuals studied. Thus, chronic or repeated exposure to antigen may contribute to the longevity of the HIV-1 reservoir by stimulating the clonal expansion of latently infected CD4+ T cells.

Highlights

HIV-1 persists in memory CD4+ T cells including HIV-1, CMV, and influenza specific T cells (Douek et al, 2002; Jones et al, 2012; Demoustier et al, 2002; Hey-Nguyen et al, 2019)
HIV-1 proviral DNA is enriched in HIV-1, CMV and influenza responsive T cells obtained from antiretroviral therapy (ART) suppressed individuals, but whether or how this might be related to clonal expansion of T cells harboring latent viruses was not examined (Hey-Nguyen et al, 2019; Kristoff et al, 2019; Henrich et al, 2017; Douek et al, 2002; Demoustier et al, 2002; Jones et al, 2012) Here we report that expanded clones of CD4+ T cells containing replication competent viruses respond to antigenic stimulation with peptides derived from viruses that cause chronic infections
Following overnight culture with HIV-gag, CMV-pp65, CEFT, or Staphylococcal enterotoxin B (SEB), activated CD4+ T cells from 8 donors were purified by cell sorting based on expression of two or more activation induced markers (AIM+: CD69, PD-L1, and 41BB (Fig. 1a, b and Supplemental Fig. 1))

Summary

Introduction

HIV-1 persists in memory CD4+ T cells including HIV-1, CMV, and influenza specific T cells (Douek et al, 2002; Jones et al, 2012; Demoustier et al, 2002; Hey-Nguyen et al, 2019). HIV-1 can become latent in a small number of infected CD4+ T cells, and these cells constitute a latent reservoir that is the principle barrier to HIV-1 cure. A significant fraction of the circulating latent reservoir is composed of expanded clones of CD4+ T cells containing replication competent proviruses (50% or greater (Bui et al, 2017; Hosmane et al, 2017; Lorenzi et al, 2016; Simonetti et al, 2016; Reeves et al, 2018)). Understanding the basis for latently infected T cell clonal expansion is important for learning how to control and potentially eliminate the reservoir

Methods

Results

Conclusion