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

• Published in: The Journal of clinical investigation 2022-04, Vol.132 (7)
• Main Authors: Duette, Gabriel, Hiener, Bonnie, Morgan, Hannah, Mazur, Fernando G, Mathivanan, Vennila, Horsburgh, Bethany A, Fisher, Katie, Tong, Orion, Lee, Eunok, Ahn, Haelee, Shaik, Ansari, Fromentin, Remi, Hoh, Rebecca, Bacchus-Souffan, Charline, Nasr, Najla, Cunningham, Anthony L, Hunt, Peter W, Chomont, Nicolas, Turville, Stuart G, Deeks, Steven G, Kelleher, Anthony D, Schlub, Timothy E, Palmer, Sarah
• Format: Article
• Language: English
• Subjects: Antiviral agents; Care and treatment; Development and progression; Genetic aspects; Health aspects; HIV (Viruses); HIV infection; Immunologic memory; Patient outcomes; T cells; Viral proteins
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI154422

Despite long-term antiretroviral therapy (ART), HIV-1 persists within a reservoir of [CD4.sup.+] 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.sup.+] 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.sup.+] T cells when compared with naive, central, and transitional memory [CD4.sup.+] 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.