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 Milush; Renee M. Van der Sluis; Sarah Palmer; Steven G. Deeks; Paul U. Cameron; Vanessa Evans; Sharon R. Lewin

doi:10.1016/j.xcrm.2022.100766

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 journal › Article › Research › peer-review

3 Citations (Scopus)

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 (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.

Original language	English
Article number	100766
Number of pages	19
Journal	Cell Reports Medicine
Volume	3
Issue number	10
DOIs	https://doi.org/10.1016/j.xcrm.2022.100766
Publication status	Published - 18 Oct 2022

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.xcrm.2022.100766Licence: CC BY-NC-ND

Cite this

Rasmussen, T. A., Zerbato, J. M., Rhodes, A., Tumpach, C., Dantanarayana, A., McMahon, J. H., Lau, J. S. Y., Chang, J. J., Gubser, C., Brown, W., Hoh, R., Krone, M., Pascoe, R., Chiu, C. Y., Bramhall, M., Lee, H. J., Haque, A., Fromentin, R., Chomont, N., ... Lewin, S. R. (2022). Memory CD4⁺ T cells that co-express PD1 and CTLA4 have reduced response to activating stimuli facilitating HIV latency. Cell Reports Medicine, 3(10), [100766]. https://doi.org/10.1016/j.xcrm.2022.100766

@article{a882335c2dca4b949b1670ae2383d681,

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

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 (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.",

keywords = "CTLA4, HIV, HIV cure, HIV latency, HIV persistence, HIV reservoirs, immune checkpoints, PD1, T cell exhaustion",

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

year = "2022",

month = oct,

day = "18",

doi = "10.1016/j.xcrm.2022.100766",

language = "English",

volume = "3",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "10",

}

Rasmussen, TA, Zerbato, JM, Rhodes, A, Tumpach, C, Dantanarayana, A, McMahon, JH , Lau, JSY, Chang, JJ, Gubser, C, Brown, W, Hoh, R, Krone, M, Pascoe, R, Chiu, CY, Bramhall, M, Lee, HJ, Haque, A, Fromentin, R, Chomont, N, Milush, J, Van der Sluis, RM, Palmer, S, Deeks, SG, Cameron, PU, Evans, V & Lewin, SR 2022, 'Memory CD4⁺ T cells that co-express PD1 and CTLA4 have reduced response to activating stimuli facilitating HIV latency', Cell Reports Medicine, vol. 3, no. 10, 100766. https://doi.org/10.1016/j.xcrm.2022.100766

TY - JOUR

T1 - Memory CD4+ T cells that co-express PD1 and CTLA4 have reduced response to activating stimuli facilitating HIV latency

AU - Rasmussen, Thomas A.

AU - Zerbato, Jennifer M.

AU - Rhodes, Ajantha

AU - Tumpach, Carolin

AU - Dantanarayana, Ashanti

AU - McMahon, James H.

AU - Lau, Jillian S.Y.

AU - Chang, J. Judy

AU - Gubser, Celine

AU - Brown, Wendy

AU - Hoh, Rebecca

AU - Krone, Melissa

AU - Pascoe, Rachel

AU - Chiu, Chris Y.

AU - Bramhall, Michael

AU - Lee, Hyun Jae

AU - Haque, Ashraful

AU - Fromentin, Rèmi

AU - Chomont, Nicolas

AU - Milush, Jeffrey

AU - Van der Sluis, Renee M.

AU - Palmer, Sarah

AU - Deeks, Steven G.

AU - Cameron, Paul U.

AU - Evans, Vanessa

AU - Lewin, Sharon R.

PY - 2022/10/18

Y1 - 2022/10/18

N2 - 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.

AB - 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.

KW - CTLA4

KW - HIV

KW - HIV cure

KW - HIV latency

KW - HIV persistence

KW - HIV reservoirs

KW - immune checkpoints

KW - PD1

KW - T cell exhaustion

UR - http://www.scopus.com/inward/record.url?scp=85140414854&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2022.100766

DO - 10.1016/j.xcrm.2022.100766

M3 - Article

C2 - 36198308

AN - SCOPUS:85140414854

SN - 2666-3791

VL - 3

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 10

M1 - 100766

ER -

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