Memory CD4+ T cells that co-express PD1 and CTLA4 have reduced response to activating stimuli facilitating HIV latency

Thomas A. Rasmussen, Jennifer M. Zerbato, Ajantha Rhodes, Carolin Tumpach, Ashanti Dantanarayana, James H. McMahon, Jillian S.Y. Lau, J. Judy Chang, Celine Gubser, Wendy Brown, Rebecca Hoh, Melissa Krone, Rachel Pascoe, Chris Y. Chiu, Michael Bramhall, Hyun Jae Lee, Ashraful Haque, Rèmi Fromentin, Nicolas Chomont, Jeffrey MilushRenee M. Van der Sluis, Sarah Palmer, Steven G. Deeks, Paul U. Cameron, Vanessa Evans, Sharon R. Lewin

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Programmed cell death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4) suppress CD4+ T cell activation and may promote latent HIV infection. By performing leukapheresis (n = 21) and lymph node biopsies (n = 8) in people with HIV on antiretroviral therapy (ART) and sorting memory CD4+ T cells into subsets based on PD1/CTLA4 expression, we investigate the role of PD1 and CTLA 4 in HIV persistence. We show that double-positive (PD1+CTLA4+) cells in blood contain more HIV DNA compared with double-negative (PD1CTLA4) cells but still have a lower proportion of cells producing multiply spliced HIV RNA after stimulation as well as reduced upregulation of T cell activation and proliferation markers. Transcriptomics analyses identify differential expression of key genes regulating T cell activation and proliferation with MAF, KLRB1, and TIGIT being upregulated in double-positive compared with double-negative cells, whereas FOS is downregulated. We conclude that, in addition to being enriched for HIV DNA, double-positive cells are characterized by negative signaling and a reduced capacity to respond to stimulation, favoring HIV latency.

Original languageEnglish
Article number100766
JournalCell Reports Medicine
Volume3
Issue number10
DOIs
StatePublished - 18 Oct 2022
Externally publishedYes

Keywords

  • CTLA4
  • HIV
  • HIV cure
  • HIV latency
  • HIV persistence
  • HIV reservoirs
  • PD1
  • T cell exhaustion
  • immune checkpoints

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