{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:06:50Z","timestamp":1791875210621,"version":"4.3.4"},"reference-count":48,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T00:00:00Z","timestamp":1694131200000},"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 (NIH)","doi-asserted-by":"publisher","award":["R21 AI102771"],"award-info":[{"award-number":["R21 AI102771"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health (NIH)","doi-asserted-by":"publisher","award":["R01 AI080564"],"award-info":[{"award-number":["R01 AI080564"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health (NIH)","doi-asserted-by":"publisher","award":["5T32HL086345-08"],"award-info":[{"award-number":["5T32HL086345-08"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health (NIH)","doi-asserted-by":"publisher","award":["P30 CA16042"],"award-info":[{"award-number":["P30 CA16042"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health (NIH)","doi-asserted-by":"publisher","award":["P30 AI28697"],"award-info":[{"award-number":["P30 AI28697"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health (NIH)","doi-asserted-by":"publisher","award":["D13-LA-394"],"award-info":[{"award-number":["D13-LA-394"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"California HIV\/AIDS Research Program (CHRP)","award":["R21 AI102771"],"award-info":[{"award-number":["R21 AI102771"]}]},{"name":"California HIV\/AIDS Research Program (CHRP)","award":["R01 AI080564"],"award-info":[{"award-number":["R01 AI080564"]}]},{"name":"California HIV\/AIDS Research Program (CHRP)","award":["5T32HL086345-08"],"award-info":[{"award-number":["5T32HL086345-08"]}]},{"name":"California HIV\/AIDS Research Program (CHRP)","award":["P30 CA16042"],"award-info":[{"award-number":["P30 CA16042"]}]},{"name":"California HIV\/AIDS Research Program (CHRP)","award":["P30 AI28697"],"award-info":[{"award-number":["P30 AI28697"]}]},{"name":"California HIV\/AIDS Research Program (CHRP)","award":["D13-LA-394"],"award-info":[{"award-number":["D13-LA-394"]}]},{"name":"UCLA AIDS Institute, the James B. Pendleton Charitable Trust, and the McCarthy Family Foundation","award":["R21 AI102771"],"award-info":[{"award-number":["R21 AI102771"]}]},{"name":"UCLA AIDS Institute, the James B. Pendleton Charitable Trust, and the McCarthy Family Foundation","award":["R01 AI080564"],"award-info":[{"award-number":["R01 AI080564"]}]},{"name":"UCLA AIDS Institute, the James B. Pendleton Charitable Trust, and the McCarthy Family Foundation","award":["5T32HL086345-08"],"award-info":[{"award-number":["5T32HL086345-08"]}]},{"name":"UCLA AIDS Institute, the James B. Pendleton Charitable Trust, and the McCarthy Family Foundation","award":["P30 CA16042"],"award-info":[{"award-number":["P30 CA16042"]}]},{"name":"UCLA AIDS Institute, the James B. Pendleton Charitable Trust, and the McCarthy Family Foundation","award":["P30 AI28697"],"award-info":[{"award-number":["P30 AI28697"]}]},{"name":"UCLA AIDS Institute, the James B. Pendleton Charitable Trust, and the McCarthy Family Foundation","award":["D13-LA-394"],"award-info":[{"award-number":["D13-LA-394"]}]},{"name":"JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA","award":["R21 AI102771"],"award-info":[{"award-number":["R21 AI102771"]}]},{"name":"JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA","award":["R01 AI080564"],"award-info":[{"award-number":["R01 AI080564"]}]},{"name":"JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA","award":["5T32HL086345-08"],"award-info":[{"award-number":["5T32HL086345-08"]}]},{"name":"JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA","award":["P30 CA16042"],"award-info":[{"award-number":["P30 CA16042"]}]},{"name":"JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA","award":["P30 AI28697"],"award-info":[{"award-number":["P30 AI28697"]}]},{"name":"JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA","award":["D13-LA-394"],"award-info":[{"award-number":["D13-LA-394"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Regeneration of functional na\u00efve T lymphocytes following the onset of human immunodeficiency virus (HIV) infection remains a crucial issue for people living with HIV (PLWH), even when adhering to antiretroviral therapy (ART). Thus far, reports on the impact of HIV-1 infection on the entry of thymic precursors and the egress of functional na\u00efve T lymphocytes to and from the thymus are limited. We examined the impact of HIV-1 on Sphingosine-1-phosphate (S1P) signaling, which governs the egress of functional na\u00efve thymocytes from the thymus to the periphery. Using in vitro experiments with primary human thymocytes and in vivo and ex vivo studies with humanized mice, we show that HIV-1 infection results in upregulation of the expression of S1P receptor 1 (S1PR1) in the human thymus. Intriguingly, this upregulation occurs during intrathymic infection (direct infection of the human thymic implant) as well as systemic infection in humanized mice. Moreover, considering the dysregulation of pro- and anti-inflammatory cytokines in infected thymi, the increased expression of S1PR1 in response to in vitro exposure to Interferon-Beta (IFN-\u03b2) and Tumor Necrosis Factor-Alpha (TNF-\u03b1) indicates that cytokine dysregulation following HIV infection may contribute to upregulation of S1PR1. Finally, an increased presence of CD3hiCD69\u2212 (fully mature) as well as CD3hiCD69+ (less mature) T cells in the spleen during HIV infection in humanized mice, combined with earlier expression of S1PR1 during thymocyte development, suggests that upregulation of S1PR1 may translate to increased or accelerated egress from the thymus. The egress of thymocytes that are not functionally mature from the thymus to peripheral blood and lymphoid organs may have implications for the immune function of PLWH.<\/jats:p>","DOI":"10.3390\/ijms241813865","type":"journal-article","created":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T09:00:52Z","timestamp":1694422852000},"page":"13865","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["HIV-1 Infection Results in Sphingosine-1-Phosphate Receptor 1 Dysregulation in the Human Thymus"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3833-2433","authenticated-orcid":false,"given":"Rachel S.","family":"Resop","sequence":"first","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA"},{"name":"UCLA AIDS Institute and Center for AIDS Research, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley","family":"Salvatore","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn J.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent R.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Blom","sequence":"additional","affiliation":[{"name":"Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7255-0226","authenticated-orcid":false,"given":"Dimitrios N.","family":"Vatakis","sequence":"additional","affiliation":[{"name":"UCLA AIDS Institute and Center for AIDS Research, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christel H.","family":"Uittenbogaart","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA"},{"name":"UCLA AIDS Institute and Center for AIDS Research, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Pediatrics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095, USA"},{"name":"Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1086\/695852","article-title":"The absence of CD4+ T cell count recovery despite receipt of virologically suppressive highly active antiretroviral therapy: Clinical risk, immunological gaps, and therapeutic options","volume":"48","author":"Gazzola","year":"2009","journal-title":"Clin. 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