{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T23:08:40Z","timestamp":1788390520800,"version":"build-2803163510"},"reference-count":75,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"823","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,11,5]]},"abstract":"<jats:p>\n                    Plasmacytoid dendritic cells (pDCs) rapidly produce type I interferon (IFN-I) in response to acute virus infections. During chronic HIV-1 infection, persistent activation of pDCs contributes to inflammatory diseases. Combination antiretroviral therapy (cART) effectively suppresses HIV-1 replication and prolongs the life span of people living with HIV-1 (PLWH). The persistence of viral reservoir cells under cART, however, is associated with suboptimal immune reconstitution, impaired anti-HIV immunity, and non\u2013AIDS-defining inflammatory diseases through unclear mechanisms. We report here that pDC depletion in HIV-infected humanized mice with suppressive cART alleviated HIV-associated inflammation, reversed T cell immune exhaustion, enhanced HIV-specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses, and reduced HIV-1 reservoirs in lymphoid and nonlymphoid tissues through CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell\u2013dependent mechanisms. Specifically, pDC depletion in the mice led to an increase in TCF-1\n                    <jats:sup>+<\/jats:sup>\n                    PD-1\n                    <jats:sup>+<\/jats:sup>\n                    Tim-3\n                    <jats:sup>\u2212<\/jats:sup>\n                    stem-like memory CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in HIV-infected lymphoid tissues, which correlated with a reduction in the HIV-1 reservoir. We further showed that pDCs suppressed the polyfunctional activity of anti-HIV stem-like memory CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells isolated from PLWH in vitro. As in the HIV-infected humanized mice, pDC depletion or IFN-I blockade functionally rescued the stem-like memory CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, enhancing their anti-HIV responses. Combination therapy with PD-1 blockade further improved stem-like memory T cell function both in vitro and in HIV-infected humanized mice. Our findings indicate that HIV-induced inflammatory pDCs impair anti-HIV stem-like memory CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses and suggest that the combination of pDC depletion with PD-1 immune checkpoint blockade represents a candidate therapeutic approach to treating HIV-1 infection and its associated inflammatory diseases.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adr3930","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T18:58:26Z","timestamp":1762369106000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":11,"title":["Depletion of plasmacytoid dendritic cells rescues HIV-reactive stem-like CD8\n                    <sup>+<\/sup>\n                    T cells during chronic HIV-1 infection"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2076-609X","authenticated-orcid":true,"given":"Guangming","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Human Virology, Department of Pharmacology and Physiology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA."},{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4915-867X","authenticated-orcid":true,"given":"Yaoxian","family":"Lou","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, Department of Pharmacology and Physiology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Ma","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."},{"name":"Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, Hubei 430000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1757-1411","authenticated-orcid":true,"given":"Haisheng","family":"Yu","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0621-6753","authenticated-orcid":true,"given":"Ourania","family":"Tsahouridis","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6110-9531","authenticated-orcid":true,"given":"Xiuting","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, Department of Pharmacology and Physiology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA."},{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5936-6371","authenticated-orcid":true,"given":"Masaya","family":"Funaki","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, Department of Pharmacology and Physiology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA."},{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4405-2593","authenticated-orcid":true,"given":"James","family":"Ahodantin","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, Department of Pharmacology and Physiology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA."},{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2960-441X","authenticated-orcid":true,"given":"Wenwen","family":"Bi","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwen","family":"Chen","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, 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Brad","family":"Jones","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7471-0812","authenticated-orcid":true,"given":"Shyamasundaran","family":"Kottilil","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1346-9388","authenticated-orcid":true,"given":"Poonam","family":"Mathur","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0350-5560","authenticated-orcid":true,"given":"Lishan","family":"Su","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, Department of Pharmacology and Physiology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA."},{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."},{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-042909-093756"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/v11030200"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir659"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20181359"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707244104"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2004"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11904-019-00444-7"},{"key":"e_1_3_2_9_2","first-page":"3544","article-title":"Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response","volume":"119","author":"Jacquelin B.","year":"2009","unstructured":"B. Jacquelin, V. Mayau, B. Targat, A. S. Liovat, D. Kunkel, G. Petitjean, M. A. Dillies, P. Roques, C. Butor, G. Silvestri, L. D. Giavedoni, P. Lebon, F. Barre-Sinoussi, A. Benecke, M. C. Muller-Trutwin, Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J. Clin. Invest. 119, 3544\u20133555 (2009).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_2_10_2","first-page":"3556","article-title":"Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys","volume":"119","author":"Bosinger S. E.","year":"2009","unstructured":"S. E. Bosinger, Q. Li, S. N. Gordon, N. R. Klatt, L. Duan, L. Xu, N. Francella, A. Sidahmed, A. J. Smith, E. M. Cramer, M. Zeng, D. Masopust, J. V. Carlis, L. Ran, T. H. Vanderford, M. Paiardini, R. B. Isett, D. A. Baldwin, J. G. Else, S. I. Staprans, G. Silvestri, A. T. Haase, D. J. Kelvin, Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys. J. Clin. Invest. 119, 3556\u20133572 (2009).","journal-title":"J. Clin. 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