Memory CD4+ T cells that co-express PD1 and CTLA4 have reduced response to activating stimuli facilitating HIV latency
Authors:
- Rasmussen, Thomas A.
- Zerbato, Jennifer M.
- Rhodes, Ajantha
- Tumpach, Carolin
- Dantanarayana, Ashanti
- McMahon, James H.
- Lau, Jillian S.Y.
- Chang, J. Judy
- Gubser, Celine
- Brown, Wendy
- Hoh, Rebecca
- Krone, Melissa
- Pascoe, Rachel
- Chiu, Chris Y.
- Bramhall, Michael
- Lee, Hyun Jae
- Haque, Ashraful
- Fromentin, Rèmi
- Chomont, Nicolas
- Milush, Jeffrey
- Van der Sluis, Renee M.
- Palmer, Sarah
- Deeks, Steven G.
- Cameron, Paul U.
- Evans, Vanessa
- Lewin, Sharon R.
Details:
Cell Reports Medicine, Volume 3, Issue 10, 2022-10-18
Article Link: Click here
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 (PD1−CTLA4−) 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.