{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:47:09Z","timestamp":1790128029567,"version":"4.0.1"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T00:00:00Z","timestamp":1659052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI068634, AI068636, AI106701, HL117713"],"award-info":[{"award-number":["AI068634, AI068636, AI106701, HL117713"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Inflammation associated with increased risk of comorbidities persists in people living with HIV (PWH) on combination antiretroviral therapy (ART). A recent placebo-controlled trial of low-dose methotrexate (MTX) in PWH found that numbers of total CD4 and CD8 T cells decreased in the low-dose MTX arm. In this report we analyzed T cell phenotypes and additional plasma inflammatory indices in samples from the trial. We found that cycling (Ki67+) T cells lacking Bcl-2 were reduced by MTX but plasma inflammatory cytokines were largely unaffected. In a series of <jats:italic>in vitro<\/jats:italic> experiments to further investigate the mechanisms of MTX activity, we found that MTX did not inhibit effector cytokine production but inhibited T cell proliferation downstream of mTOR activation, mitochondrial function, and cell cycle entry. This inhibitory effect was reversible with folinic acid, suggesting low-dose MTX exerts anti-inflammatory effects <jats:italic>in vivo<\/jats:italic> in PWH largely by blocking T cell proliferation <jats:italic>via<\/jats:italic> dihydrofolate reductase inhibition, yet daily administration of folic acid did not rescue this effect in trial participants. Our findings identify the main mechanism of action of this widely used anti-inflammatory medicine in PWH and may provide insight into how MTX works in the setting of other inflammatory conditions.<\/jats:p>","DOI":"10.3389\/fimmu.2022.924718","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T13:08:22Z","timestamp":1659100102000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Methotrexate Inhibits T Cell Proliferation but Not Inflammatory Cytokine Expression to Modulate Immunity in People Living With HIV"],"prefix":"10.3389","volume":"13","author":[{"given":"Michael L.","family":"Freeman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian M.","family":"Clagett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Moisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunice","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles D.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benigno","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James H.","family":"Stein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven G.","family":"Deeks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith S.","family":"Currier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscilla Y.","family":"Hsue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald D.","family":"Anthony","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard H.","family":"Calabrese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather J.","family":"Ribaudo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael M.","family":"Lederman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jis200","article-title":"Immunologic Basis of Cardiovascular Disease in Hiv-Infected Adults","author":"Hsue","year":"2012","journal-title":"J Infect Dis"},{"key":"B2","doi-asserted-by":"publisher","first-page":"200","DOI":"10.3390\/v11030200","article-title":"Immune Activation, Inflammation, and Non-Aids Co-Morbidities in Hiv-Infected Patients Under Long-Term Art","volume":"11","author":"Zicari","year":"2019","journal-title":"Viruses"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu254","article-title":"Soluble Markers of Inflammation and Coagulation But Not T-Cell Activation Predict Non-Aids-Defining Morbid Events During Suppressive Antiretroviral Treatment","volume":"210","author":"Tenorio","year":"2014","journal-title":"J Infect Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2010.143396","article-title":"The Risk of Myocardial Infarction in Rheumatoid Arthritis and Diabetes Mellitus: A Danish Nationwide Cohort Study","volume":"70","author":"Lindhardsen","year":"2011","journal-title":"Ann Rheumatic Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-200726","article-title":"Risk of Incident Cardiovascular Events in Patients With Rheumatoid Arthritis: A Meta-Analysis of Observational Studies","volume":"71","author":"Avina-Zubieta","year":"2012","journal-title":"Ann Rheumatic Dis"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2010.5","article-title":"Methotrexate\u2013How Does It Really Work","volume":"6","author":"Chan","year":"2010","journal-title":"Nat Rev Rheumatol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keg323","article-title":"Inhibition of Cytokine Production by Methotrexate. 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