The Journal of Clinical Investigation (Apr 2022)

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

  • 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

Journal volume & issue
Vol. 132, no. 7

Abstract

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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.

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