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Through integrated single-cell RNA sequencing and functional validation in HIV-1-infected humanized mice with combination antiretroviral therapy (cART) and IFN-I signaling blockade, we reveal IFN-I-induced dysfunction of natural killer (NK) cells and group 3 innate lymphoid cells (ILC3s). Mechanistically, the IFN-I-CD9 axis drives NK cells toward a decidual NK cell-like phenotype, impairing their cytotoxic activity. Furthermore, IFNAR blockade rescues ILC3 functionality, which is critical for IL-17\/IL-22-mediated antimicrobial defense and mucosal barrier maintenance. Our study delineates IFN-I-driven immunosuppression across innate lymphocyte compartments and proposes the targeted modulation of this pathway to enhance antiviral and mucosal immunity in HIV-1 management.<\/jats:p>","DOI":"10.3390\/v17081099","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T13:20:09Z","timestamp":1754659209000},"page":"1099","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Persistent Type I Interferon Signaling Impairs Innate Lymphoid Cells During HIV-1 Infection Under Suppressive ART"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4646-6928","authenticated-orcid":false,"given":"Runpeng","family":"Han","sequence":"first","affiliation":[{"name":"State Key Laboratory of Virology and Biosafety, Department of Infectious Diseases, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1757-1411","authenticated-orcid":false,"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"},{"name":"Infectious Disease Center, Guangzhou Eighth People\u2019s Hospital, Guangzhou Medical University, Guangzhou 510440, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangming","family":"Li","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":"Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Department of Pharmacology, 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":false,"given":"Lishan","family":"Su","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":"Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Cheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology and Biosafety, Department of Infectious Diseases, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China"},{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"name":"Center for AIDS Research, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1038\/nrmicro3352","article-title":"Eradicating HIV-1 infection: Seeking to clear a persistent pathogen","volume":"12","author":"Archin","year":"2014","journal-title":"Nat. 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