{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T06:15:28Z","timestamp":1773296128698,"version":"3.50.1"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,9,15]],"date-time":"2017-09-15T00:00:00Z","timestamp":1505433600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,9,15]],"date-time":"2017-09-15T00:00:00Z","timestamp":1505433600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Poor CD4<jats:sup>+<\/jats:sup> T-cell recovery after cART has been associated with skewed T-cell maturation, inflammation and immunosenescence; however, T-cell functionality in those individuals has not been fully characterized. In the present study, we assessed T-cell function by assessing cytokine production after polyclonal, CMV and HIV stimulations of T-cells from ART-suppressed HIV-infected individuals with CD4<jats:sup>+<\/jats:sup> T-cell counts &gt;350 cells\/\u03bcL (immunoconcordants) or &lt;350 cells\/\u03bcL (immunodiscordants). A group of HIV-uninfected individuals were also included as controls. Since CMV co-infection significantly affected T-cell maturation and polyfunctionality, only CMV<jats:sup>+<\/jats:sup> individuals were analyzed. Despite their reduced and skewed CD4<jats:sup>+<\/jats:sup> T-cell compartment, immunodiscordant individuals showed preserved polyclonal and HIV-specific responses. However, CMV response in immunodiscordant participants was significantly different from immunoconcordant or HIV-seronegative individuals. In immunodiscordant subjects, the magnitude of IFN-\u03b3<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> and IL-2<jats:sup>+<\/jats:sup> CD4<jats:sup>+<\/jats:sup> T-cells in response to CMV was higher and differently associated with the CD4<jats:sup>+<\/jats:sup> T-cell maturation profile., showing an increased frequency of na\u00efve, central memory and EMRA CMV-specific CD4<jats:sup>+<\/jats:sup> T-cells. In conclusion, CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T-cell polyfunctionality was not reduced in immunodiscordant individuals, although heightened CMV-specific immune responses, likely related to subclinical CMV reactivations, may be contributing to the skewed T-cell maturation and the higher risk of clinical progression observed in those individuals.<\/jats:p>","DOI":"10.1038\/s41598-017-12013-2","type":"journal-article","created":{"date-parts":[[2017,9,11]],"date-time":"2017-09-11T13:15:44Z","timestamp":1505135744000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Preserved immune functionality and high CMV-specific T-cell responses in HIV-infected individuals with poor CD4+ T-cell immune recovery"],"prefix":"10.1038","volume":"7","author":[{"given":"Elisabet","family":"G\u00f3mez-Mora","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabet","family":"Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2577-856X","authenticated-orcid":false,"given":"Victor","family":"Urrea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Massanella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordi","family":"Puig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugenia","family":"Negredo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bonaventura","family":"Clotet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2225-0217","authenticated-orcid":false,"given":"Juli\u00e0","family":"Blanco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9941-6828","authenticated-orcid":false,"given":"Cecilia","family":"Cabrera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,9,15]]},"reference":[{"key":"12013_CR1","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1056\/NEJM199803263381301","volume":"338","author":"FJ Palella","year":"1998","unstructured":"Palella, F. J. et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N. Engl. J. Med. \n                           338, 853\u2013860 (1998).","journal-title":"N. Engl. J. Med."},{"key":"12013_CR2","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1097\/00002030-199807000-00011","volume":"12","author":"C Piketty","year":"1998","unstructured":"Piketty, C. et al. Discrepant responses to triple combination antiretroviral therapy in advanced HIV disease. AIDS \n                           12, 745\u2013750 (1998).","journal-title":"AIDS"},{"key":"12013_CR3","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1086\/597093","volume":"48","author":"CF Kelley","year":"2009","unstructured":"Kelley, C. F. et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis \n                           48, 787\u2013794 (2009).","journal-title":"Clin Infect Dis"},{"key":"12013_CR4","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1586\/1744666X.2013.842897","volume":"9","author":"M Massanella","year":"2013","unstructured":"Massanella, M., Negredo, E., Clotet, B. & Blanco, J. Immunodiscordant responses to HAART\u2013mechanisms and consequences. Expert Rev Clin Immunol \n                           9, 1135\u20131149 (2013).","journal-title":"Expert Rev Clin Immunol"},{"key":"12013_CR5","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1097\/QAD.0b013e328337b957","volume":"24","author":"M Massanella","year":"2010","unstructured":"Massanella, M. et al. CD4 T-cell hyperactivation and susceptibility to cell death determine poor CD4 T-cell recovery during suppressive HAART. AIDS \n                           24, 959\u2013968 (2010).","journal-title":"AIDS"},{"key":"12013_CR6","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1093\/jac\/dkp248","volume":"64","author":"S Molina-Pinelo","year":"2009","unstructured":"Molina-Pinelo, S. et al. Premature immunosenescence in HIV-infected patients on highly active antiretroviral therapy with low-level CD4 T cell repopulation. J. Antimicrob. Chemother. \n                           64, 579\u2013588 (2009).","journal-title":"J. Antimicrob. Chemother."},{"key":"12013_CR7","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1086\/651689","volume":"50","author":"E Negredo","year":"2010","unstructured":"Negredo, E. et al. Nadir CD4 T Cell Count as Predictor and High CD4 T Cell Intrinsic Apoptosis as Final Mechanism of Poor CD4 T Cell Recovery in Virologically Suppressed HIV\u2010Infected Patients: Clinical Implications. Clin Infect Dis \n                           50, 1300\u20131308 (2010).","journal-title":"Clin Infect Dis"},{"key":"12013_CR8","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1086\/319678","volume":"183","author":"JP Viard","year":"2001","unstructured":"Viard, J. P. et al. Influence of age on CD4 cell recovery in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy: evidence from the EuroSIDA study. J. Infect. Dis. \n                           183, 1290\u20131294 (2001).","journal-title":"J. Infect. Dis."},{"key":"12013_CR9","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1097\/01.aids.0000242819.72839.db","volume":"20","author":"G Marchetti","year":"2006","unstructured":"Marchetti, G. et al. Comparative analysis of T-cell turnover and homeostatic parameters in HIV-infected patients with discordant immune-virological responses to HAART. AIDS \n                           20, 1727\u20131736 (2006).","journal-title":"AIDS"},{"key":"12013_CR10","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1093\/infdis\/jir507","volume":"204","author":"MM Lederman","year":"2011","unstructured":"Lederman, M. M. et al. Immunologic Failure Despite Suppressive Antiretroviral Therapy Is Related to Activation and Turnover of Memory CD4 Cells. J. Infect. Dis \n                           204, 1217\u20131226 (2011).","journal-title":"J. Infect. Dis"},{"key":"12013_CR11","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1097\/QAD.0b013e328339cf40","volume":"24","author":"G Marchetti","year":"2010","unstructured":"Marchetti, G. et al. Skewed T-cell maturation and function in HIV-infected patients failing CD4+ recovery upon long-term virologically suppressive HAART. AIDS \n                           24, 1455\u20131460 (2010).","journal-title":"AIDS"},{"key":"12013_CR12","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1097\/QAI.0b013e3181ca3f7c","volume":"53","author":"C Erikstrup","year":"2010","unstructured":"Erikstrup, C. et al. T-cell dysfunction in HIV-1-infected patients with impaired recovery of CD4 cells despite suppression of viral replication. J. Acquir. Immune Defic. Syndr. \n                           53, 303\u2013310 (2010).","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"12013_CR13","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-015-0601-2","volume":"13","author":"M Massanella","year":"2015","unstructured":"Massanella, M. et al. Increased ex vivo cell death of central memory CD4 T cells in treated HIV infected individuals with unsatisfactory immune recovery. J Transl Med \n                           13, 230 (2015).","journal-title":"J Transl Med"},{"key":"12013_CR14","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1093\/jac\/dkr594","volume":"67","author":"G M\u00e9ndez-Lagares","year":"2012","unstructured":"M\u00e9ndez-Lagares, G. et al. Differential alterations of the CD4 and CD8 T cell subsets in HIV-infected patients on highly active antiretroviral therapy with low CD4 T cell restoration. J. Antimicrob. Chemother. \n                           67, 1228\u20131237 (2012).","journal-title":"J. Antimicrob. Chemother."},{"key":"12013_CR15","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-11-43","volume":"11","author":"D Nakanjako","year":"2011","unstructured":"Nakanjako, D. et al. High T-cell immune activation and immune exhaustion among individuals with suboptimal CD4 recovery after 4 years of antiretroviral therapy in an African cohort. BMC Infect. Dis. \n                           11, 43 (2011).","journal-title":"BMC Infect. Dis."},{"key":"12013_CR16","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1097\/00007435-199810000-00006","volume":"25","author":"M Robain","year":"1998","unstructured":"Robain, M., Carr\u00e9, N., Dussaix, E., Salmon-Ceron, D. & Meyer, L. Incidence and sexual risk factors of cytomegalovirus seroconversion in HIV-infected subjects. The SEROCO Study Group. Sex Transm Dis \n                           25, 476\u2013480 (1998).","journal-title":"Sex Transm Dis"},{"key":"12013_CR17","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/S0140-6736(89)90312-7","volume":"2","author":"A Webster","year":"1989","unstructured":"Webster, A. et al. Cytomegalovirus infection and progression towards AIDS in haemophiliacs with human immunodeficiency virus infection. Lancet \n                           2, 63\u201366 (1989).","journal-title":"Lancet"},{"key":"12013_CR18","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.exger.2016.02.005","volume":"77","author":"M Weltevrede","year":"2016","unstructured":"Weltevrede, M., Eilers, R., de Melker, H. E. & van Baarle, D. Cytomegalovirus persistence and T-cell immunosenescence in people aged fifty and older: A systematic review. Exp. Gerontol. \n                           77, 87\u201395 (2016).","journal-title":"Exp. Gerontol."},{"key":"12013_CR19","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1093\/infdis\/jiv071","volume":"212","author":"A Huygens","year":"2015","unstructured":"Huygens, A. et al. Functional Exhaustion Limits CD4+ and CD8+ T-Cell Responses to Congenital Cytomegalovirus Infection. J. Infect. Dis. \n                           212, 484\u2013494 (2015).","journal-title":"J. Infect. Dis."},{"key":"12013_CR20","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.1093\/infdis\/jir060","volume":"203","author":"PW Hunt","year":"2011","unstructured":"Hunt, P. W. et al. Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J. Infect. Dis \n                           203, 1474\u20131483 (2011).","journal-title":"J. Infect. Dis"},{"key":"12013_CR21","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1093\/infdis\/jiv148","volume":"212","author":"S Gianella","year":"2015","unstructured":"Gianella, S., Massanella, M., Wertheim, J. O. & Smith, D. M. The Sordid Affair Between Human Herpesvirus and HIV. J. Infect. Dis. \n                           212, 845\u2013852 (2015).","journal-title":"J. Infect. Dis."},{"issue":"Suppl 2","key":"12013_CR22","doi-asserted-by":"publisher","first-page":"S67","DOI":"10.1093\/infdis\/jiw217","volume":"214","author":"S Gianella","year":"2016","unstructured":"Gianella, S. & Letendre, S. Cytomegalovirus and HIV: A Dangerous Pas de Deux. J. Infect. Dis. \n                           214(Suppl 2), S67\u201374 (2016).","journal-title":"J. Infect. Dis."},{"key":"12013_CR23","doi-asserted-by":"crossref","unstructured":"Naeger, D. M. et al. Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease. PLoS ONE \n                           5 (2010).","DOI":"10.1371\/journal.pone.0008886"},{"key":"12013_CR24","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1097\/QAD.0b013e32834640e6","volume":"25","author":"V Appay","year":"2011","unstructured":"Appay, V. et al. Old age and anti-cytomegalovirus immunity are associated with altered T-cell reconstitution in HIV-1-infected patients. AIDS \n                           25, 1813\u20131822 (2011).","journal-title":"AIDS"},{"key":"12013_CR25","doi-asserted-by":"publisher","first-page":"2275","DOI":"10.1097\/QAD.0b013e3280108704","volume":"20","author":"PY Hsue","year":"2006","unstructured":"Hsue, P. Y. et al. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS \n                           20, 2275\u20132283 (2006).","journal-title":"AIDS"},{"key":"12013_CR26","doi-asserted-by":"publisher","first-page":"1788","DOI":"10.1093\/infdis\/jis276","volume":"205","author":"CM Parrinello","year":"2012","unstructured":"Parrinello, C. M. et al. Cytomegalovirus immunoglobulin G antibody is associated with subclinical carotid artery disease among HIV-infected women. J. Infect. Dis \n                           205, 1788\u20131796 (2012).","journal-title":"J. Infect. Dis"},{"key":"12013_CR27","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1097\/QAD.0000000000001412","volume":"31","author":"EU Patel","year":"2017","unstructured":"Patel, E. U. et al. Elevated cytomegalovirus IgG antibody levels are associated with HIV-1 disease progression and immune activation. AIDS \n                           31, 807\u2013813 (2017).","journal-title":"AIDS"},{"key":"12013_CR28","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1111\/j.1365-2249.2008.03785.x","volume":"155","author":"S Chidrawar","year":"2009","unstructured":"Chidrawar, S. et al. Cytomegalovirus-seropositivity has a profound influence on the magnitude of major lymphoid subsets within healthy individuals. Clin. Exp. Immunol \n                           155, 423\u2013432 (2009).","journal-title":"Clin. Exp. Immunol"},{"key":"12013_CR29","doi-asserted-by":"publisher","first-page":"2746","DOI":"10.1099\/vir.0.036004-0","volume":"92","author":"E Derhovanessian","year":"2011","unstructured":"Derhovanessian, E. et al. Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4+ and CD8+ T-cells in humans. J. Gen. Virol. \n                           92, 2746\u20132756 (2011).","journal-title":"J. Gen. Virol."},{"key":"12013_CR30","doi-asserted-by":"publisher","first-page":"3675","DOI":"10.1128\/JVI.79.6.3675-3683.2005","volume":"79","author":"G Almanzar","year":"2005","unstructured":"Almanzar, G. et al. Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. Journal of Virology \n                           79, 3675\u20133683 (2005).","journal-title":"Journal of Virology"},{"key":"12013_CR31","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1007\/s11357-011-9240-6","volume":"34","author":"MA Moro-Garc\u00eda","year":"2012","unstructured":"Moro-Garc\u00eda, M. A. et al. Relationship between functional ability in older people, immune system status, and intensity of response to CMV. Age (Dordr) \n                           34, 479\u2013495 (2012).","journal-title":"Age (Dordr)"},{"key":"12013_CR32","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1093\/infdis\/jiw371","volume":"214","author":"M Bajwa","year":"2016","unstructured":"Bajwa, M. et al. Functional Diversity of Cytomegalovirus-Specific T Cells Is Maintained in Older People and Significantly Associated With Protein Specificity and Response Size. J. Infect. Dis. \n                           214, 1430\u20131437 (2016).","journal-title":"J. Infect. Dis."},{"key":"12013_CR33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003076","volume":"8","author":"A Lelic","year":"2012","unstructured":"Lelic, A. et al. The polyfunctionality of human memory CD8+ T cells elicited by acute and chronic virus infections is not influenced by age. PLoS Pathog. \n                           8, e1003076 (2012).","journal-title":"PLoS Pathog."},{"key":"12013_CR34","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.jiac.2016.09.003","volume":"23","author":"R Minami","year":"2017","unstructured":"Minami, R., Takahama, S., Kaku, Y. & Yamamoto, M. Addition of maraviroc to antiretroviral therapy decreased interferon-\u03b3 mRNA in the CD4+ T cells of patients with suboptimal CD4+ T-cell recovery. J. Infect. Chemother \n                           23, 29\u201334 (2017).","journal-title":"J. Infect. Chemother"},{"key":"12013_CR35","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1097\/QAI.0000000000001392","volume":"75","author":"R Casetti","year":"2017","unstructured":"Casetti, R. et al. HIV-Specific CD8 T Cells Producing CCL-4 Are Associated With Worse Immune Reconstitution During Chronic Infection. J. Acquir. Immune Defic. Syndr. \n                           75, 338\u2013344 (2017).","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"12013_CR36","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1038\/44385","volume":"401","author":"F Sallusto","year":"1999","unstructured":"Sallusto, F., Lenig, D., F\u00f6rster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature \n                           401, 708\u2013712 (1999).","journal-title":"Nature"},{"key":"12013_CR37","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00498","volume":"4","author":"SR Roff","year":"2014","unstructured":"Roff, S. R., Noon-Song, E. N. & Yamamoto, J. K. The Significance of Interferon-\u03b3 in HIV-1 Pathogenesis, Therapy, and Prophylaxis. Front Immunol \n                           4, 498 (2014).","journal-title":"Front Immunol"},{"key":"12013_CR38","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1038\/nature04790","volume":"441","author":"MA Williams","year":"2006","unstructured":"Williams, M. A., Tyznik, A. J. & Bevan, M. J. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature \n                           441, 890\u2013893 (2006).","journal-title":"Nature"},{"key":"12013_CR39","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1089\/vim.2009.0069","volume":"23","author":"N Sachdeva","year":"2010","unstructured":"Sachdeva, N. et al. Poor lymphoproliferative responses with low proportion of Gag-specific CD8 TEMRA cells in HIV-1-infected patients showing immunological and virological discordance despite prolonged suppression of plasma viremia. Viral Immunol. \n                           23, 49\u201361 (2010).","journal-title":"Viral Immunol."},{"key":"12013_CR40","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1093\/jac\/dkl049","volume":"57","author":"SF Stone","year":"2006","unstructured":"Stone, S. F., Price, P. & French, M. A. Cytomegalovirus (CMV)-specific CD8+ T cells in individuals with HIV infection: correlation with protection from CMV disease. J. Antimicrob. Chemother. \n                           57, 585\u2013588 (2006).","journal-title":"J. Antimicrob. Chemother."},{"key":"12013_CR41","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1093\/cid\/cit252","volume":"57","author":"S Gianella","year":"2013","unstructured":"Gianella, S. et al. Shedding of HIV and human herpesviruses in the semen of effectively treated HIV-1-infected men who have sex with men. CLIN INFECT DIS \n                           57, 441\u2013447 (2013).","journal-title":"CLIN INFECT DIS"},{"key":"12013_CR42","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1128\/JVI.00873-11","volume":"86","author":"R Lachmann","year":"2012","unstructured":"Lachmann, R. et al. Polyfunctional T cells accumulate in large human cytomegalovirus-specific T cell responses. Journal of Virology \n                           86, 1001\u20131009 (2012).","journal-title":"Journal of Virology"},{"key":"12013_CR43","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1089\/aid.2015.0085","volume":"31","author":"KM Erlandson","year":"2015","unstructured":"Erlandson, K. M. et al. Physical function impairment of older, HIV-infected adults is associated with cytomegalovirus immunoglobulin response. AIDS Research and Human Retroviruses \n                           31, 905\u2013912 (2015).","journal-title":"AIDS Research and Human Retroviruses"},{"key":"12013_CR44","doi-asserted-by":"publisher","first-page":"7818","DOI":"10.1128\/JVI.00831-14","volume":"88","author":"S Gianella","year":"2014","unstructured":"Gianella, S. et al. Cytomegalovirus replication in semen is associated with higher levels of proviral HIV DNA and CD4+ T cell activation during antiretroviral treatment. Journal of Virology \n                           88, 7818\u20137827 (2014).","journal-title":"Journal of Virology"},{"key":"12013_CR45","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1038\/8400","volume":"5","author":"CJ Pitcher","year":"1999","unstructured":"Pitcher, C. J. et al. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat. Med. \n                           5, 518\u2013525 (1999).","journal-title":"Nat. Med."},{"key":"12013_CR46","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/35065118","volume":"410","author":"P Champagne","year":"2001","unstructured":"Champagne, P. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature \n                           410, 106\u2013111 (2001).","journal-title":"Nature"},{"key":"12013_CR47","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1038\/nm0402-379","volume":"8","author":"V Appay","year":"2002","unstructured":"Appay, V. et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat. Med \n                           8, 379\u2013385 (2002).","journal-title":"Nat. Med"},{"key":"12013_CR48","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.4049\/jimmunol.174.2.1037","volume":"174","author":"A Harari","year":"2005","unstructured":"Harari, A., Vallelian, F., Meylan, P. R. & Pantaleo, G. Functional heterogeneity of memory CD4 T cell responses in different conditions of antigen exposure and persistence. J. Immunol. \n                           174, 1037\u20131045 (2005).","journal-title":"J. Immunol."},{"key":"12013_CR49","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1093\/infdis\/jis230","volume":"205","author":"G M\u00e9ndez-Lagares","year":"2012","unstructured":"M\u00e9ndez-Lagares, G. et al. Severe immune dysregulation affects CD4+CD25(hi)FoxP3+ regulatory T cells in HIV-infected patients with low-level CD4 T-cell repopulation despite suppressive highly active antiretroviral therapy. Journal of Infectious Diseases \n                           205, 1501\u20131509 (2012).","journal-title":"Journal of Infectious Diseases"},{"key":"12013_CR50","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1093\/cid\/ciq202","volume":"52","author":"PW Hunt","year":"2011","unstructured":"Hunt, P. W. et al. HIV-specific CD4+ T cells may contribute to viral persistence in HIV controllers. CLIN INFECT DIS \n                           52, 681\u2013687 (2011).","journal-title":"CLIN INFECT DIS"},{"key":"12013_CR51","doi-asserted-by":"crossref","unstructured":"Cockerham, L. R. et al. CD4+ and CD8+ T cell activation are associated with HIV DNA in resting CD4+ T cells. PLoS ONE \n                           9 (2014).","DOI":"10.1371\/journal.pone.0110731"},{"key":"12013_CR52","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1038\/nm.1972","volume":"15","author":"N Chomont","year":"2009","unstructured":"Chomont, N. et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat. Med \n                           15, 893\u2013900 (2009).","journal-title":"Nat. Med"},{"key":"12013_CR53","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/417095a","volume":"417","author":"DC Douek","year":"2002","unstructured":"Douek, D. C. et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature \n                           417, 95\u201398 (2002).","journal-title":"Nature"},{"key":"12013_CR54","doi-asserted-by":"publisher","first-page":"1819","DOI":"10.1128\/JVI.02968-13","volume":"88","author":"C Riou","year":"2014","unstructured":"Riou, C. et al. Differential impact of magnitude, polyfunctional capacity, and specificity of HIV-specific CD8+ T cell responses on HIV set point. Journal of Virology \n                           88, 1819\u20131824 (2014).","journal-title":"Journal of Virology"},{"key":"12013_CR55","doi-asserted-by":"publisher","first-page":"2473","DOI":"10.1084\/jem.20070784","volume":"204","author":"JR Almeida","year":"2007","unstructured":"Almeida, J. R. et al. Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J. Exp. Med. \n                           204, 2473\u20132485 (2007).","journal-title":"J. Exp. Med."},{"key":"12013_CR56","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1002\/eji.200737768","volume":"38","author":"MG Duvall","year":"2008","unstructured":"Duvall, M. G. et al. Polyfunctional T cell responses are a hallmark of HIV-2 infection. Eur. J. Immunol. \n                           38, 350\u2013363 (2008).","journal-title":"Eur. J. Immunol."},{"key":"12013_CR57","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1084\/jem.20050882","volume":"202","author":"AW Sylwester","year":"2005","unstructured":"Sylwester, A. W. et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J. Exp. Med. \n                           202, 673\u2013685 (2005).","journal-title":"J. Exp. Med."},{"key":"12013_CR58","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1128\/CVI.00479-07","volume":"15","author":"A Weinberg","year":"2008","unstructured":"Weinberg, A. et al. In vitro cell-mediated immune responses of human immunodeficiency virus-infected and -uninfected individuals to whole cytomegalovirus antigens and their subunits. Clin. Vaccine Immunol. \n                           15, 1398\u20131409 (2008).","journal-title":"Clin. Vaccine Immunol."},{"key":"12013_CR59","doi-asserted-by":"publisher","first-page":"1709","DOI":"10.1086\/340637","volume":"185","author":"F Kern","year":"2002","unstructured":"Kern, F. et al. Cytomegalovirus (CMV) phosphoprotein 65 makes a large contribution to shaping the T cell repertoire in CMV-exposed individuals. J. Infect. Dis. \n                           185, 1709\u20131716 (2002).","journal-title":"J. Infect. Dis."},{"key":"12013_CR60","doi-asserted-by":"publisher","first-page":"1676","DOI":"10.1002\/1521-4141(200006)30:6<1676::AID-IMMU1676>3.0.CO;2-V","volume":"30","author":"F Kern","year":"2000","unstructured":"Kern, F. et al. Analysis of CD8 T cell reactivity to cytomegalovirus using protein-spanning pools of overlapping pentadecapeptides. Eur. J. Immunol. \n                           30, 1676\u20131682 (2000).","journal-title":"Eur. J. Immunol."},{"key":"12013_CR61","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/S0022-1759(01)00416-1","volume":"255","author":"HT Maecker","year":"2001","unstructured":"Maecker, H. T. et al. Use of overlapping peptide mixtures as antigens for cytokine flow cytometry. Journal of Immunological Methods \n                           255, 27\u201340 (2001).","journal-title":"Journal of Immunological Methods"},{"key":"12013_CR62","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1128\/CDLI.8.2.303-313.2001","volume":"8","author":"J Baran","year":"2001","unstructured":"Baran, J., Kowalczyk, D., Oz\u00f3g, M. & Zembala, M. Three-color flow cytometry detection of intracellular cytokines in peripheral blood mononuclear cells: comparative analysis of phorbol myristate acetate-ionomycin and phytohemagglutinin stimulation. Clin. Diagn. Lab. Immunol. \n                           8, 303\u2013313 (2001).","journal-title":"Clin. Diagn. Lab. Immunol."},{"key":"12013_CR63","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/0014-4827(92)90360-K","volume":"201","author":"CM Petersen","year":"1992","unstructured":"Petersen, C. M., Christensen, E. I., Andresen, B. S. & M\u00f8ller, B. K. Internalization, lysosomal degradation and new synthesis of surface membrane CD4 in phorbol ester-activated T-lymphocytes and U-937 cells. Exp. Cell Res. \n                           201, 160\u2013173 (1992).","journal-title":"Exp. Cell Res."},{"key":"12013_CR64","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1002\/cyto.a.21015","volume":"79A","author":"M Roederer","year":"2011","unstructured":"Roederer, M., Nozzi, J. L. & Nason, M. C. SPICE: Exploration and analysis of post-cytometric complex multivariate datasets. Cytometry \n                           79A, 167\u2013174 (2011).","journal-title":"Cytometry"},{"key":"12013_CR65","doi-asserted-by":"crossref","unstructured":"Larsen, M. et al. Evaluating cellular polyfunctionality with a novel polyfunctionality index. PLoS ONE \n                           7 (2012).","DOI":"10.1371\/journal.pone.0042403"},{"key":"12013_CR66","unstructured":"Larsen, M. http:\/\/www.funkycells.com\/main (2016)."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12013-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12013-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12013-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T11:06:23Z","timestamp":1671793583000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12013-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,15]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["12013"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-12013-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,15]]},"assertion":[{"value":"25 May 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 August 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"E.G.M., M.M., E.G., V.U., J.P., J.B., E.N. and C.C. report no disclosures. B.C. have served as a consultant to and\/or have received research grant support from Gilead, Janssen, MSD, ViiV, BMS.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"11711"}}