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This latent viral reservoir serves as a source of plasma viral rebound following treatment interruption, thus requiring lifelong adherence to ART. Additionally, challenges remain related not only to access to therapy but also to a higher prevalence of comorbidities with an inflammatory etiology in treated HIV-1+ individuals, underscoring the need to explore therapeutic alternatives that achieve sustained virologic remission in the absence of ART. Natural killer (NK) cells are uniquely positioned to positively impact antiviral immunity, in part due to the pleiotropic nature of their effector functions, including the acquisition of memory-like features, and, therefore, hold great promise for transforming HIV-1 therapeutic modalities. In addition to defining the ability of NK cells to contribute to HIV-1 control, this review provides a basic immunologic understanding of the impact of HIV-1 infection and ART on the phenotypic and functional character of NK cells. We further delineate the qualities of \u201cmemory\u201d NK cell populations, as well as the impact of HCMV on their induction and subsequent expansion in HIV-1 infection. We conclude by highlighting promising avenues for optimizing NK cell responses to improve HIV-1 control and effect a functional cure, including blockade of inhibitory NK receptors, TLR agonists to promote latency reversal and NK cell activation, CAR NK cells, BiKEs\/TriKEs, and the role of HIV-1-specific bNAbs in NK cell\u2013mediated ADCC activity against HIV-1-infected cells.<\/jats:p>","DOI":"10.1093\/jleuko\/qiac007","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T04:53:21Z","timestamp":1673844801000},"page":"109-138","source":"Crossref","is-referenced-by-count":27,"title":["Mapping the interplay between NK cells and HIV: therapeutic implications"],"prefix":"10.1093","volume":"113","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 , Pittsburgh, PA 15261 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robbie B","family":"Mailliard","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, University of Pittsburgh , Pittsburgh, PA 15261 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,1,16]]},"reference":[{"issue":"2","key":"2023020116345801600_qiac007-B1","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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