The HIV-1 proviral landscape reveals that Nef contributes to HIV-1 persistence in effector memory CD4+ T cells

Abstract

Despite long-term antiretroviral therapy (ART), HIV-1 persists within a reservoir of CD4 + T cells that contribute to viral rebound if treatment is interrupted. Identifying the cellular populations that contribute to the HIV-1 reservoir and understanding the mechanisms of viral persistence are necessary to achieve an effective cure. In this regard, through Full-Length Individual Proviral Sequencing, we observed that the HIV-1 proviral landscape was different and changed with time on ART across naive and memory CD4 + T cell subsets isolated from 24 participants. We found that the proportion of genetically intact HIV-1 proviruses was higher and persisted over time in effector memory CD4 + T cells when compared with naive, central, and transitional memory CD4 + T cells. Interestingly, we found that escape mutations remained stable over time within effector memory T cells during therapy. Finally, we provided evidence that Nef plays a role in the persistence of genetically intact HIV-1. These findings posit effector memory T cells as a key component of the HIV-1 reservoir and suggest Nef as an attractive therapeutic target.

Distinct gene expression by expanded clones of quiescent memory CD4+ T cells harboring intact latent HIV-1 proviruses

“…We find that expanded clones of memory CD4 + T cells that carry intact integrated HIV-1 proviruses are enriched among cells that express a transcriptional program that is found in CD4 + T EM cells. Our data is in accordance with studies showing enrichment of genetically intact proviruses in the CD4 + T EM compartment but extends previous observations by revealing the transcriptional program of resting latent cells 33, 68 .…”

Identification of HIV-reservoir cells with reduced susceptibility to antibody-dependent immune response

“…The HIV reservoir has a complex and heterogeneous nature, where each of the subsets that compose the viral reservoir contributes differently to viral persistence ( Gálvez et al, 2021 ; Astorga-Gamaza and Buzon, 2021 ); i.e., central memory cells are one of the main populations contributing to the total reservoir size ( Chomont et al, 2009 ), effector memory cells support HIV transcription ( Grau-Expósito et al, 2017 ) and contain higher proportions of intact viral regions ( Duette et al, 2022 ; Musick et al, 2019 ; Hiener et al, 2017 ), and memory stem cells and resident memory T cells are potentially long-lived niches for HIV ( Buzon et al, 2014 ; Cantero-Pérez et al, 2019 ). Unfortunately, knowledge on the establishment, maintenance, and composition of the reservoir remains incomplete, and the identification of markers to exclusively target persistent HIV-infected cells remains elusive ( Darcis et al, 2019 ; Neidleman et al, 2020 ).…”

A histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV infected cells

“…Generally, CD4 T cells further along in this stated order possess more effector functions but lose proliferative and self-renewal potential. These changes in CD4 T cells are guided by transcriptional programs that define and maintain subset identity; importantly, studies show that the latent reservoir is enriched in longer-lived memory cells(Manganaro et al, 2018; Soriano-Sarabia et al, 2014) (T CM and T SCM ) and that cells with effector character more readily express viral gene products(Bradley et al, 2018; Kulpa et al, 2019; Wonderlich et al, 2019), although this association is not detected in every study of PLWH and may depend on the cohort or method of latent reservoir quantification(Duette et al, 2022; Kwon et al, 2020). We therefore sought to define the association between viral latency and CD4 T-cell memory subsets in our model system.…”