Impact of Early Antiretroviral Treatment on Tissue-Resident Memory CD4+ T Cells in the Gastrointestinal Tract
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Tissue resident memory CD4+ T cells (CD4+ TRM) are long-lived, seldom-circulating cells that reside for long periods in most tissues. TRM can mount rapid, antigen-specific responses to pathogens and contribute to mucosal barrier homeostasis by regulating commensal interactions. At the intestinal mucosa, the main site of early HIV replication, CD4+ TRM may serve as virus targets; however, limited data are available regarding their dynamics during acute HIV-1 infection and antiretroviral treatment. METHODS: Nested cross-sectional study within a longitudinal cohort. RESULTS: Sigmoid CD4+ TRM (CD69+CD103+) had a higher expression of CCR5 compared to CD4+ non-TRM (CD69-CD103-), suggestive of increased susceptibility to HIV-1 infection. Consistent with this, sigmoid CD4+ TRM but not CD4+ non-TRM were depleted/non-replenished despite long-term ART, regardless of the Fiebig (F) stage treatment was initiated during acute HIV infection. In contrast, overall sigmoid CD4+ T-cells were comparable in abundance with people living without HIV if treatment was initiated in FI/II, but were significantly decreased if treatment was initiated >FIII, suggesting preferential early depletion/non-replenishment of CD4+ TRM. The loss/non-replenishment of sigmoid CD4+ TRM was associated with a lower abundance of short-chain fatty acid producing commensal bacteria that are crucial for the maintenance of mucosal homeostasis, a higher abundance of opportunistic pathobionts Desulfovibrio, and increased soluble biomarkers of systemic inflammation that drive non-AIDS mortality. CONCLUSION: Sigmoid CD4+ TRM may be early mucosal targets of HIV-1 infection and that their persistent depletion contributes to decreased mucosal barrier function, warranting development of therapeutic strategies that can restore CD4+ TRM during HIV treatment.
Authors: Sinmanus Vimonpatranon, Aloysious Ssemaganda, Yuwadee Phuang-Ngern, Chayada Sajjaweerawan, Putita Saetun, Termeh Shakery, Suchada Sukhumvittaya, Shruti Rathore, Rungsun Rerknimitr, Phillip K Ehrenberg, Daina Eiser, Nisakorn Ratnaratorn, Lydie Trautmann, Sandra Choi, Giulia Severini, Rasmi Thomas, Carlo Sacdalan, Suteeraporn Pinyakorn, Jintanat Ananworanich, Jessica Cowden, Denise Hsu, Sandhya Vasan, Nittaya Phanuphak, Lyle R McKinnon, Alexandra Schuetz, the RV254/SEARCH010 and RV304/SEARCH013 study groups, Nittaya Phanuphak, Nipat Teeratakulpisarn, Supanit Pattanachaiwit, Eugene Kroon, Carlo Sacdalan, Somchai Sriplienchan, Mark de Souza, Ponpen Tantivitayakul, Nitiya Chomchey, Duanghathai Suttichom, Kultida Poltavee, Jintana Intasan, Tassanee Luekasemsuk, Hathairat Savadsuk, Somporn Tipsuk, Suwanna Puttamsawin, Khunthalee Benjapornpong, Nisakorn Ratnaratorn, Kamonkan Tangnaree, Chutharat Munkong, Rommanus Thaimanee, Patcharin Eamyoung, Sasiwimol Ubolyam, Supranee Buranapraditkun, Sukalya Lerdlum, Sopark Manasnayakorn, Rugsun Rerknimitr, Sunee Sirivichayakul, Phandee Wattanaboonyongcharoen, Siriwat Akapirat, Bessara Nuntapinit, Nantana Tantibul, Nampueng Churikanont, Saowanit Getchalarat, Julie Ake, Trevor Crowell, Donn Colby, Ellen Turk, Oratai Butterworth, Mark Milazzo, Robert Clifford, Leigh Anne Eller
Institutions: Armed Forces Research Institute of Medical Science, University of Manitoba, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Walter Reed Army Institute of Research, Henry M. Jackson Foundation, Amsterdam UMC Location University of Amsterdam, Amsterdam Institute for Global Health and Development, University of Nairobi, Centre for the AIDS Programme of Research in South Africa
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,763
Award: G8602338186
OpenAlex ID: W7168578145