{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T19:16:09Z","timestamp":1793214969627,"version":"4.5.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T00:00:00Z","timestamp":1656979200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    CD8 T cell exhaustion is a hallmark of HIV-1 infection, characterized by phenotypic and functional CD8 T cell abnormalities that persist despite years of effective antiretroviral treatment (ART). More recently, the importance of cellular metabolism in shaping T cell antiviral function has emerged as a crucial aspect of immunotherapeutics aimed at re-invigorating exhausted CD8 T cells but remains under-investigated in HIV-1 infection. To gain a better insight into this process and identify new targets for effective CD8 T cell restoration we examined the metabolic profile of exhausted CD8 T cells in HIV-1 infection. We show that relative to HIV-1 elite controllers (EC) and HIV-1 seronegative donors, CD8 T cells from HIV-1 viraemic individuals are skewed toward a PD-1\n                    <jats:sup>hi<\/jats:sup>\n                    EOMES\n                    <jats:sup>hi<\/jats:sup>\n                    T-bet\n                    <jats:sup>low<\/jats:sup>\n                    TIGIT\n                    <jats:sup>+<\/jats:sup>\n                    phenotype that is maintained during ART. This exhausted signature is enriched in HIV-specific CD8 T cells, compared to CMV-specific CD8 T cell populations, and further delineated by higher expression of the glucose transporter, Glut-1, impaired mitochondrial function and biogenesis, reflecting underlying metabolic defects. A notable improvement in antiviral HIV-specific CD8 T cell function was elicited\n                    <jats:italic>via<\/jats:italic>\n                    mitochondrial antioxidant treatment in combination with pharmacological modulation of mitochondrial dynamics and IL-15 treatment. These findings identify mitochondria as promising targets for combined reconstitution therapies in HIV-1 infection.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.908697","type":"journal-article","created":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T09:20:51Z","timestamp":1657012851000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":40,"title":["Functional Restoration of Exhausted CD8 T Cells in Chronic HIV-1 Infection by Targeting Mitochondrial Dysfunction"],"prefix":"10.3389","volume":"13","author":[{"given":"Aljawharah","family":"Alrubayyi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elia","family":"Moreno-Cubero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Hameiri-Bowen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Rowland-Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Schurich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitra","family":"Peppa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12823","article-title":"T-Cell Exhaustion in HIV Infection","volume":"292","author":"Craig","year":"2019","journal-title":"Immunol Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05115","article-title":"PD-1 Expression on HIV-Specific T Cells is Associated With T-Cell Exhaustion and Disease Progression","volume":"443","author":"Day","year":"2006","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nm1482","article-title":"Upregulation of PD-1 Expression on HIV-Specific CD8+ T Cells Leads to Reversible Immune Dysfunction","volume":"12","author":"Trautmann","year":"2006","journal-title":"Nat Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01153-09","article-title":"Defective Human Immunodeficiency Virus-Specific CD8+ T-Cell Polyfunctionality, Proliferation, and Cytotoxicity are Not Restored by Antiretroviral Therapy","volume":"83","author":"Migueles","year":"2009","journal-title":"J Virol"},{"key":"B5","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2019.01896","article-title":"CD8(+) T-Cell Response to HIV Infection in the Era of Antiretroviral Therapy","volume":"10","author":"Perdomo-Celis","year":"2019","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.04.005","article-title":"Metabolic Pathways in Immune Cell Activation and Quiescence","volume":"38","author":"Pearce","year":"2013","journal-title":"Immunity"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151159","article-title":"T Cell Metabolism Drives Immunity","volume":"212","author":"Buck","year":"2015","journal-title":"J Exp Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.immuni.2014.06.005","article-title":"Memory CD8(+) T Cells Use Cell-Intrinsic Lipolysis to Support the Metabolic Programming Necessary for Development","volume":"41","author":"O\u2019Sullivan","year":"2014","journal-title":"Immunity"},{"key":"B9","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.immuni.2011.12.007","article-title":"Mitochondrial Respiratory Capacity is a Critical Regulator of CD8+ T Cell Memory Development","volume":"36","author":"van derWindt","year":"2012","journal-title":"Immunity"},{"key":"B10","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1126\/science.aaa7516","article-title":"T Cell Metabolism. 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