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However, evaluation of this effect could be confounded by age-related immune processes such as decreased thymus output, increased immune activation and exhaustion. Here, we established a semi-mechanistic population model simultaneously describing na\u00efve and memory CD4+ T-cell trajectories in 122 participants. Covariate analysis accounting for immune activation showed that older age was significantly associated with faster apparent elimination rate of the na\u00efve T-cells. In addition, female sex predicted slower apparent elimination rate of memory T-cells. Simulations showed that the median maximal CD4+ T-cell count on ART treatment was 593 cells\/\u03bcL (IQR 442-794) in patients aged 50\u2009years or above and 738 cells\/\u03bcL (IQR 548-1002) in patients aged 18-35\u2009years. The differences in the percentage of subjects achieving sufficient immune reconstitution (CD4+ T-cell count&gt;\u2009500 cells\/\u03bcL) between the two age groups were 15, 21 and 26% at year 1, 4\u2009years and steady state, respectively, suggesting that advanced age may have a greater impact on long-term CD4+ T-cell recovery.<\/jats:p>","DOI":"10.1186\/s12979-021-00260-x","type":"journal-article","created":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T02:03:20Z","timestamp":1641175400000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["The effect of age on CD4+ T-cell recovery in HIV-suppressed adult participants: a sub-study from AIDS Clinical Trial Group (ACTG) A5321 and the Bone Loss and Immune Reconstitution (BLIR) study"],"prefix":"10.1186","volume":"19","author":[{"given":"Jingxian","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kehmia","family":"Titanji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anandi N.","family":"Sheth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh","family":"Gandhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"McMahon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ighovwerha","family":"Ofotokun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Neale","family":"Weitzmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"De Paris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3500-5819","authenticated-orcid":false,"given":"Julie B.","family":"Dumond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,3]]},"reference":[{"issue":"12","key":"260_CR1","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1002\/phar.1670","volume":"35","author":"J Jourjy","year":"2015","unstructured":"Jourjy J, Dahl K, Huesgen E. Antiretroviral treatment efficacy and safety in older HIV-infected adults. Pharmacotherapy. 2015;35(12):1140\u201351.","journal-title":"Pharmacotherapy"},{"issue":"17","key":"260_CR2","doi-asserted-by":"publisher","first-page":"2331","DOI":"10.1097\/QAD.0b013e32831883f9","volume":"22","author":"AH Greenbaum","year":"2008","unstructured":"Greenbaum AH, et al. Effect of age and HAART regimen on clinical response in an urban cohort of HIV-infected individuals. AIDS. 2008;22(17):2331\u20139.","journal-title":"AIDS"},{"issue":"18","key":"260_CR3","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1001\/archinte.163.18.2187","volume":"163","author":"GR Kaufmann","year":"2003","unstructured":"Kaufmann GR, et al. CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: the Swiss HIV cohort study. Arch Intern Med. 2003;163(18):2187\u201395.","journal-title":"Arch Intern Med"},{"issue":"5","key":"260_CR4","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1097\/QAI.0b013e31821e9f21","volume":"57","author":"X Li","year":"2011","unstructured":"Li X, et al. CD4+ T-cell counts and plasma HIV-1 RNA levels beyond 5 years of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2011;57(5):421\u20138.","journal-title":"J Acquir Immune Defic Syndr"},{"issue":"3","key":"260_CR5","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1086\/510746","volume":"44","author":"RD Moore","year":"2007","unstructured":"Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis. 2007;44(3):441\u20136.","journal-title":"Clin Infect Dis"},{"issue":"4","key":"260_CR6","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1111\/j.1468-1293.2012.01053.x","volume":"14","author":"ST Wright","year":"2013","unstructured":"Wright ST, et al. Ageing and long-term CD4 cell count trends in HIV-positive patients with 5 years or more combination antiretroviral therapy experience. HIV Med. 2013;14(4):208\u201316.","journal-title":"HIV Med"},{"issue":"9","key":"260_CR7","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1093\/cid\/cir552","volume":"53","author":"T Li","year":"2011","unstructured":"Li T, et al. Reduced thymic output is a major mechanism of immune reconstitution failure in HIV-infected patients after long-term antiretroviral therapy. Clin Infect Dis. 2011;53(9):944\u201351.","journal-title":"Clin Infect Dis"},{"key":"260_CR8","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/j.1600-065X.2006.00493.x","volume":"216","author":"RM Ribeiro","year":"2007","unstructured":"Ribeiro RM, Perelson AS. Determining thymic output quantitatively: using models to interpret experimental T-cell receptor excision circle (TREC) data. Immunol Rev. 2007;216:21\u201334.","journal-title":"Immunol Rev"},{"issue":"43","key":"260_CR9","doi-asserted-by":"publisher","first-page":"18333","DOI":"10.1073\/pnas.0910139106","volume":"106","author":"H Tsukamoto","year":"2009","unstructured":"Tsukamoto H, et al. Age-associated increase in lifespan of naive CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects. 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J Infect Dis. 2003;187(10):1534\u201343.","journal-title":"J Infect Dis"},{"issue":"2","key":"260_CR12","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1310\/hct1402-61","volume":"14","author":"XY Zhang","year":"2013","unstructured":"Zhang XY, et al. Immune activation while on potent antiretroviral therapy can predict subsequent CD4+T-cell increases through 15 years of treatment. Hiv Clin Trials. 2013;14(2):61\u20137.","journal-title":"Hiv Clin Trials"},{"issue":"4","key":"260_CR13","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1093\/infdis\/jir787","volume":"205","author":"J Lewis","year":"2012","unstructured":"Lewis J, et al. Age and CD4 count at initiation of antiretroviral therapy in HIV-infected children: effects on long-term T-cell reconstitution. 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Effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy in HIV-1-positive subjects: results from ACTG 384. J Acquir Immune Defic Syndr. 2006;42(4):426\u201334.","journal-title":"J Acquir Immune Defic Syndr"},{"key":"260_CR27","doi-asserted-by":"publisher","first-page":"e99","DOI":"10.1038\/cddis.2010.77","volume":"1","author":"NW Cummins","year":"2010","unstructured":"Cummins NW, Badley AD. Mechanisms of HIV-associated lymphocyte apoptosis: 2010. Cell Death Dis. 2010;1:e99.","journal-title":"Cell Death Dis"},{"issue":"4","key":"260_CR28","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1111\/j.1365-2567.2010.03255.x","volume":"129","author":"JS Yi","year":"2010","unstructured":"Yi JS, Cox MA, Zajac AJ. T-cell exhaustion: characteristics, causes and conversion. Immunology. 2010;129(4):474\u201381.","journal-title":"Immunology"},{"issue":"4","key":"260_CR29","doi-asserted-by":"publisher","first-page":"e1006285","DOI":"10.1371\/journal.ppat.1006285","volume":"13","author":"RT Gandhi","year":"2017","unstructured":"Gandhi RT, et al. Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation. PLoS Pathog. 2017;13(4):e1006285.","journal-title":"PLoS Pathog"},{"key":"260_CR30","doi-asserted-by":"publisher","first-page":"S85","DOI":"10.1007\/s10928-017-9508-2","volume":"44","author":"JX Chen","year":"2017","unstructured":"Chen JX, et al. Population modeling of longitudinal CD4+T cell recovery in HIV-infected participants on up to 15 years of antiretroviral therapy: the effect of aging. J Pharmacokinet Pharmacodyn. 2017;44:S85\u20136.","journal-title":"J Pharmacokinet Pharmacodyn"},{"issue":"2","key":"260_CR31","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1093\/ije\/dyr164","volume":"41","author":"Collaboration of Observational, H.I.V.E.R.E.i.E","year":"2012","unstructured":"Collaboration of Observational, H.I.V.E.R.E.i.E, et al. All-cause mortality in treated HIV-infected adults with CD4 >\/=500\/mm3 compared with the general population: evidence from a large European observational cohort collaboration. Int J Epidemiol. 2012;41(2):433\u201345.","journal-title":"Int J Epidemiol"}],"container-title":["Immunity &amp; Ageing"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12979-021-00260-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12979-021-00260-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12979-021-00260-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T14:14:10Z","timestamp":1641219250000},"score":1,"resource":{"primary":{"URL":"https:\/\/immunityageing.biomedcentral.com\/articles\/10.1186\/s12979-021-00260-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,3]]},"references-count":31,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["260"],"URL":"https:\/\/doi.org\/10.1186\/s12979-021-00260-x","relation":{},"ISSN":["1742-4933"],"issn-type":[{"value":"1742-4933","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,3]]},"assertion":[{"value":"22 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 December 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 January 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"JC is a current employee of Merck. RTG has served on scientific advisory boards for Merck and 460 Gilead. The other authors do not declare any competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"4"}}