{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:06:52Z","timestamp":1791875212350,"version":"4.3.4"},"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T00:00:00Z","timestamp":1696896000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BU 3630\/2\u20131"],"award-info":[{"award-number":["BU 3630\/2\u20131"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>For optimal functionality, immune cells require a robust and adaptable metabolic program that is fueled by dynamic mitochondrial activity. In this study, we investigate the metabolic alterations occurring in immune cells during HIV infection and antiretroviral therapy by analyzing the uptake of metabolic substrates and mitochondrial phenotypes. By delineating changes in immune cell metabolic programming during HIV, we may identify novel potential therapeutic targets to improve anti-viral immune responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>After consent and voluntary participation was confirmed, whole blood was drawn from HIV uninfected women and women with chronic HIV infection on long-term combination antiretroviral therapy (HIV\/cART). Peripheral blood mononuclear cells-derived immune cells were directly incubated with different fluorescently tagged metabolites and markers of mitochondrial activity: FITC-2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose), FITC-BODIPY (4,4-Difluoro-5,7-Dimethyl-4-Bora-3a,4a-Diaza-s-Indacene-3-Hexadecanoic Acid), FITC-MitoTracker Green and APC-MitoTracker Deep Red. The uptake of glucose and fats and the mitochondrial mass and potential were measured using flow cytometry. All values are reported quantitatively as geometric means of fluorescence intensity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      During chronic HIV infection, cellular uptake of glucose increases in HIV\n                      <jats:sup>+<\/jats:sup>\n                      dendritic cells in particular. CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells had the lowest uptake of glucose and fats compared to all other cells regardless of HIV status, while CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells took up more fatty acids. Interestingly, despite the lower utilization of glucose and fats in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells, mitochondrial mass increased in HIV\n                      <jats:sup>+<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells compared to HIV negative CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cells. HIV\n                      <jats:sup>+<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells also had the highest mitochondrial potential.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Significant disparities in the utilization of substrates by leukocytes during chronic HIV\/cART exist. Innate immune cells increased utilization of sugars and fats while adaptive immune cells displayed lower glucose and fat utilization despite having a higher mitochondrial activity. Our findings suggest that cART treated HIV-infected CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells be dysfunctional or may prefer alternative fuel sources not included in these studies. This underscores the importance of understanding the metabolic effects of HIV treatment on immune function.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0286436","type":"journal-article","created":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T13:25:56Z","timestamp":1696944356000},"page":"e0286436","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Metabolic and mitochondrial dysregulation in CD4+ T cells from HIV-positive women on combination anti-retroviral therapy"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3665-9304","authenticated-orcid":true,"given":"Matrona","family":"Akiso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5962-8845","authenticated-orcid":true,"given":"Magdalene","family":"Ameka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kewreshini","family":"Naidoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9142-886X","authenticated-orcid":true,"given":"Robert","family":"Langat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Kombo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delories","family":"Sikuku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thumbi","family":"Ndung\u2019u","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Altfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omu","family":"Anzala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9119-3167","authenticated-orcid":true,"given":"Marianne","family":"Mureithi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,10,10]]},"reference":[{"issue":"7","key":"pone.0286436.ref001","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/s42255-019-0091-2","article-title":"The metabolic tug of war between HIV and T cells","volume":"1","author":"RI Klein Geltink","year":"2019","journal-title":"Nature Metabolism"},{"key":"pone.0286436.ref002","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.3389\/fimmu.2017.01311","article-title":"Sugar or Fat?-Metabolic Requirements for Immunity to Viral Infections","volume":"8","author":"HM Shehata","year":"2017","journal-title":"Front Immunol"},{"issue":"10","key":"pone.0286436.ref003","doi-asserted-by":"crossref","first-page":"e1008957","DOI":"10.1371\/journal.ppat.1008957","article-title":"Dynamic metabolic reprogramming in dendritic cells: An early response to influenza infection that is essential for effector function","volume":"16","author":"S Rezinciuc","year":"2020","journal-title":"PLOS Pathogens"},{"key":"pone.0286436.ref004","doi-asserted-by":"crossref","first-page":"559576","DOI":"10.3389\/fimmu.2020.559576","article-title":"High Metabolic Function and Resilience of NKG2A-Educated NK Cells","volume":"11","author":"AJ Highton","year":"2020","journal-title":"Front Immunol"},{"issue":"1","key":"pone.0286436.ref005","doi-asserted-by":"crossref","first-page":"5376","DOI":"10.1038\/s41467-021-25715-z","article-title":"Metabolic requirements of NK cells during the acute response against retroviral infection","volume":"12","author":"E Littwitz-Salomon","year":"2021","journal-title":"Nature Communications"},{"issue":"1","key":"pone.0286436.ref006","doi-asserted-by":"crossref","first-page":"24129","DOI":"10.1038\/srep24129","article-title":"Cell surface Glut1 levels distinguish human CD4 and CD8 T lymphocyte subsets with distinct effector functions","volume":"6","author":"G Cretenet","year":"2016","journal-title":"Sci Rep"},{"issue":"3","key":"pone.0286436.ref007","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1097\/QAD.0000000000000128","article-title":"Increased glucose metabolic activity is associated with CD4+ T-cell activation and depletion during chronic HIV infection","volume":"28","author":"CS Palmer","year":"2014","journal-title":"Aids"},{"issue":"7","key":"pone.0286436.ref008","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/s42255-019-0084-1","article-title":"Entry of glucose- and glutamine-derived carbons into the citric acid cycle supports early steps of HIV-1 infection in CD4 T cells","volume":"1","author":"I Clerc","year":"2019","journal-title":"Nature Metabolism"},{"issue":"3","key":"pone.0286436.ref009","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.cmet.2018.11.015","article-title":"Cellular metabolism is a major determinant of HIV-1 reservoir seeding in CD4+ T cells and offers an opportunity to tackle infection","volume":"29","author":"JC Valle-Casuso","year":"2019","journal-title":"Cell metabolism"},{"issue":"2","key":"pone.0286436.ref010","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.virol.2011.04.007","article-title":"Metabolite profiles of human immunodeficiency virus infected CD4+ T cells and macrophages using LC-MS\/MS analysis","volume":"415","author":"JA Hollenbaugh","year":"2011","journal-title":"Virology"},{"issue":"1","key":"pone.0286436.ref011","doi-asserted-by":"crossref","first-page":"13683","DOI":"10.1038\/ncomms13683","article-title":"Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPAR\u03b3 directs early activation of T cells","volume":"7","author":"M Angela","year":"2016","journal-title":"Nature Communications"},{"issue":"377","key":"pone.0286436.ref012","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aag1809","article-title":"Delayed differentiation of potent effector CD8(+) T cells reducing viremia and reservoir seeding in acute HIV infection","volume":"9","author":"H Takata","year":"2017","journal-title":"Sci Transl Med"},{"issue":"1","key":"pone.0286436.ref013","doi-asserted-by":"crossref","first-page":"607","DOI":"10.4049\/jimmunol.169.1.607-a","article-title":"Dynamics of T Cell Responses in HIV Infection","volume":"169","author":"V Appay","year":"2002","journal-title":"The Journal of Immunology"},{"issue":"7","key":"pone.0286436.ref014","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/s42255-019-0081-4","article-title":"Metabolic plasticity of HIV-specific CD8+ T cells is associated with enhanced antiviral potential and natural control of HIV-1 infection","volume":"1","author":"M Angin","year":"2019","journal-title":"Nature Metabolism"},{"issue":"8","key":"pone.0286436.ref015","doi-asserted-by":"crossref","first-page":"e0183931","DOI":"10.1371\/journal.pone.0183931","article-title":"Assessment of metabolic and mitochondrial dynamics in CD4+ and CD8+ T cells in virologically suppressed HIV-positive individuals on combination antiretroviral therapy","volume":"12","author":"JJR Masson","year":"2017","journal-title":"PLoS One"},{"issue":"7","key":"pone.0286436.ref016","doi-asserted-by":"crossref","first-page":"e41129","DOI":"10.1371\/journal.pone.0041129","article-title":"HIV-1 infection and first line ART induced differential responses in mitochondria from blood lymphocytes and monocytes: the ANRS EP45 \"Aging\" study","volume":"7","author":"S Perrin","year":"2012","journal-title":"PLoS One"},{"issue":"2","key":"pone.0286436.ref017","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1097\/QAI.0000000000001175","article-title":"Distinct Mitochondrial Disturbance in CD4+T and CD8+T Cells From HIV-Infected Patients","volume":"74","author":"F Yu","year":"2017","journal-title":"J Acquir Immune Defic Syndr"},{"issue":"6","key":"pone.0286436.ref018","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1182\/blood-2006-05-021626","article-title":"Increased mitochondrial mass characterizes the survival defect of HIV-specific CD8+ T cells","volume":"109","author":"C Petrovas","year":"2006","journal-title":"Blood"},{"issue":"6204","key":"pone.0286436.ref019","doi-asserted-by":"crossref","first-page":"1250684","DOI":"10.1126\/science.1250684","article-title":"mTOR- and HIF-1\u03b1-mediated aerobic glycolysis as metabolic basis for trained immunity","volume":"345","author":"SC Cheng","year":"2014","journal-title":"Science"},{"key":"pone.0286436.ref020","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.coi.2018.09.001","article-title":"Induction of innate immune memory: the role of cellular metabolism","volume":"56","author":"J Dom\u00ednguez-Andr\u00e9s","year":"2019","journal-title":"Curr Opin Immunol"},{"key":"pone.0286436.ref021","unstructured":"Sperk M. Immunometabolic Regulation in Natural Hiv-1 Control: Karolinska Institutet (Sweden); 2022."},{"key":"pone.0286436.ref022","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2019.01306","article-title":"Role of Dendritic Cells in Natural Immune Control of HIV-1 Infection","volume":"10","author":"E Martin-Gayo","year":"2019","journal-title":"Frontiers in Immunology"},{"issue":"1","key":"pone.0286436.ref023","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/imr.12823","article-title":"T-cell exhaustion in HIV infection","volume":"292","author":"C Fenwick","year":"2019","journal-title":"Immunol Rev"},{"issue":"6","key":"pone.0286436.ref024","doi-asserted-by":"crossref","first-page":"110797","DOI":"10.1016\/j.celrep.2022.110797","article-title":"Interactomic analysis reveals a homeostatic role for the HIV restriction factor TRIM5\u03b1 in mitophagy","volume":"39","author":"B Saha","year":"2022","journal-title":"Cell Rep"},{"issue":"2","key":"pone.0286436.ref025","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.immuni.2016.07.008","article-title":"Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion","volume":"45","author":"B Bengsch","year":"2016","journal-title":"Immunity"},{"issue":"3","key":"pone.0286436.ref026","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1152\/physrev.00026.2013","article-title":"Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release","volume":"94","author":"DB Zorov","year":"2014","journal-title":"Physiological reviews"},{"issue":"2","key":"pone.0286436.ref027","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.it.2014.12.004","article-title":"Targeting T cell metabolism for therapy","volume":"36","author":"D O\u2019Sullivan","year":"2015","journal-title":"Trends Immunol"},{"issue":"16","key":"pone.0286436.ref028","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1042\/CS20160112","article-title":"Sex and gender differences in HIV-1 infection","volume":"130","author":"M Griesbeck","year":"2016","journal-title":"Clin Sci (Lond)"},{"key":"pone.0286436.ref029","doi-asserted-by":"crossref","first-page":"2936","DOI":"10.3389\/fimmu.2018.02936","article-title":"Trained Immunity-Based Vaccines: A New Paradigm for the Development of Broad-Spectrum Anti-infectious Formulations","volume":"9","author":"S S\u00e1nchez-Ram\u00f3n","year":"2018","journal-title":"Front Immunol"},{"issue":"8","key":"pone.0286436.ref030","doi-asserted-by":"crossref","DOI":"10.3390\/v14081813","article-title":"The Role of Immunometabolism in HIV-1 Pathogenicity: Links to Immune Cell Responses","volume":"14","author":"E Teer","year":"2022","journal-title":"Viruses"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0286436","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T13:26:17Z","timestamp":1696944377000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0286436"}},"subtitle":[],"editor":[{"given":"Suresh","family":"Pallikkuth","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,10,10]]},"references-count":30,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0286436","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,10]]}}}