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This is highlighted by the expansion of a rare population of FcR\u03b3\u2013 NK cells exhibiting characteristics of traditional immunologic memory in people with HIV (PWH). Although current antiretroviral therapy (ART) effectively controls HIV-1 viremia and disease progression, its impact on HIV-1\u2013associated NK cell abnormalities remains unclear. To address this, we performed a longitudinal analysis detailing conventional and memory-like NK cell characteristics in n = 60 PWH during the first 4 y of ART. Throughout this regimen, a skewed repertoire of cytokine unresponsive FcR\u03b3\u2013 memory-like NK cells persisted and accompanied an overall increase in NK surface expression of CD57 and KLRG1, suggestive of progression toward immune senescence. These traits were linked to elevated serum inflammatory biomarkers and increasing Ab titers to human CMV, with human CMV viremia detected in approximately one-third of PWH at years 1\u20134 of ART. Interestingly, 40% of PWH displayed atypical NK cell subsets, representing intermediate stages of NK-poiesis based on single-cell multiomic trajectory analysis. Our findings indicate that NK cell irregularities persist in PWH despite long-term ART, underscoring the need to better understand the causative mechanisms that prevent full restoration of immune health in PWH.<\/jats:p>","DOI":"10.4049\/jimmunol.2300672","type":"journal-article","created":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T13:00:41Z","timestamp":1711717241000},"page":"1564-1578","source":"Crossref","is-referenced-by-count":7,"title":["Persistence of a Skewed Repertoire of NK Cells in People with HIV-1 on Long-Term Antiretroviral Therapy"],"prefix":"10.1093","volume":"212","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1964-3404","authenticated-orcid":false,"given":"Renee R","family":"Anderko","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health , Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5572-858X","authenticated-orcid":false,"given":"Allison E","family":"DePuyt","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health , Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5513-3250","authenticated-orcid":false,"given":"Rhianna","family":"Bronson","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health , Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arlene C","family":"Bullotta","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgenia","family":"Aga","sequence":"additional","affiliation":[{"name":"Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health , Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald J","family":"Bosch","sequence":"additional","affiliation":[{"name":"Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health , Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R Brad","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Medicine, Weill Cornell Medicine , New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J","family":"Eron","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3737-9742","authenticated-orcid":false,"given":"John W","family":"Mellors","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh T","family":"Gandhi","sequence":"additional","affiliation":[{"name":"Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School , Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4374-3539","authenticated-orcid":false,"given":"Deborah K","family":"McMahon","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard J","family":"Macatangay","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9194-3164","authenticated-orcid":false,"given":"Charles R","family":"Rinaldo","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5501-503X","authenticated-orcid":false,"given":"Robbie B","family":"Mailliard","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,3,29]]},"reference":[{"key":"2025020405494498900_r1","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/ijc.2910160205","article-title":"Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. 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Retrovirol."},{"key":"2025020405494498900_r42","doi-asserted-by":"crossref","first-page":"2886","DOI":"10.1073\/pnas.0409872102","article-title":"Characterization of CD56\u2212\/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals","volume":"102","author":"Mavilio","year":"2005","journal-title":"Proc. Natl. Acad. Sci. 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