The HIV-1 proviral landscape reveals that Nef contributes to HIV-1 persistence in effector memory CD4+ T cells
Gabriel Duette, … , Timothy E. Schlub, Sarah Palmer
Gabriel Duette, … , Timothy E. Schlub, Sarah Palmer
Published February 8, 2022
Citation Information: J Clin Invest. 2022;132(7):e154422. https://doi.org/10.1172/JCI154422.
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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.

Authors

Gabriel Duette, Bonnie Hiener, Hannah Morgan, Fernando G. Mazur, Vennila Mathivanan, Bethany A. Horsburgh, Katie Fisher, Orion Tong, Eunok Lee, Haelee Ahn, Ansari Shaik, Rémi Fromentin, Rebecca Hoh, Charline Bacchus-Souffan, Najla Nasr, Anthony L. Cunningham, Peter W. Hunt, Nicolas Chomont, Stuart G. Turville, Steven G. Deeks, Anthony D. Kelleher, Timothy E. Schlub, Sarah Palmer

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Figure 10

Nef activity is higher in HIV-1–infected CD4+ Tem cells.

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Nef activity is higher in HIV-1–infected CD4+ Tem cells. Memory CD4+ T c...
Memory CD4+ T cells from HIV-1– donors were sorted and infected with (A and B) HIV-BaL or (C–E) HIV-NL4-3-eGFP for 5 days. (A) Representative dot plots (top) and histograms (bottom) of 10 independent experiments showing CD4 geometric mean fluorescence intensity (gMFI) in uninfected p24– and HIV-1–infected p24+ cells. (B) CD4 expression in HIV-1–infected cells was calculated as CD4 gMFI in p24+ cells relative to CD4 gMFI in p24– cells. (C) Representative dot plots (top) and histograms (bottom) of 4 independent experiments showing HLA-A*02 gMFI in uninfected eGFP– and HIV-1–infected eGFP+ cells. (D) HLA-A*02 downmodulation in HIV-1–infected cells was calculated as HLA-A*02 gMFI in eGFP+ cells relative to HLA-A*02 gMFI in eGFP– cells. (E) eGFP MFI relative to Tcm values. Data represent the mean ± SD (B) or median ± 95% CI (D and E). One-way ANOVA followed by the (B) Tukey’s HSD post test or (D and E) Kruskal-Wallis followed by Dunn’s post test were performed to determine statistical significance. Each data point represents a single donor. Tcm, central memory; Ttm, transitional memory; Tem, effector memory. *P ≤ 0.05, **P ≤ 0.01.