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Clinical data investigating the effects of injectables on HIV target cells are inconsistent or limited. No data on HIV target cells are available from head\u2010to\u2010head randomized trials comparing DMPA\u2010IM and NET\u2010EN, nor at peak progestin concentrations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method of Study<\/jats:title><jats:p>The women's health, injectable contraception, and HIV (WHICH) trial randomized women to DMPA\u2010IM or NET\u2010EN at two South African sites (2018\u20132019). Cells from blood and cytobrushes from women at one site, taken at baseline and 1 week post the 24\u2010week injection (at peak progestin levels), were analyzed by flow cytometry for select HIV\u20101 target cells (CD4<jats:sup>+<\/jats:sup> cells expressing HIV\u20101 co\u2010receptors, an integrin and\/or activation markers).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Systemically, DMPA\u2010IM and NET\u2010EN similarly reduced the frequency and number of some CD4<jats:sup>+<\/jats:sup> cells and expression of some CD4<jats:sup>+<\/jats:sup> cell surface markers. In contrast, female genital tract (FGT) results showed significantly different cell numbers between contraceptives for most cell populations; DMPA\u2010IM tended to increase, but NET\u2010EN tended to decrease cell numbers. Excluding for non\u2010study progestin use revealed significant increases in frequency and\/or number of several FGT cell populations from baseline to 25 weeks, within the DMPA\u2010IM arm.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Both contraceptives exert minimal effects on systemic CD4<jats:sup>+<\/jats:sup> cells but have differential effects in the FGT. The changes in frequency and numbers of HIV\u20101 target cells investigated, particularly after exclusion for non\u2010study progestin use, suggest that DMPA\u2010IM use may increase HIV\u20101 acquisition in the FGT compared to NET\u2010EN use.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aji.70093","type":"journal-article","created":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T08:22:32Z","timestamp":1748074952000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Injectable Contraceptives Differentially Affect Select CD4+ HIV\u20101 Target Cells in the Genital Tract but Not Systemically: Implications for HIV\u20101 Acquisition"],"prefix":"10.1111","volume":"93","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2114-1473","authenticated-orcid":false,"given":"Chanel","family":"Avenant","sequence":"first","affiliation":[{"name":"Department of Molecular and Cell Biology University of Cape Town  Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9219-7255","authenticated-orcid":false,"given":"Alexis J.","family":"Bick","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology University of Cape Town  Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0675-4606","authenticated-orcid":false,"given":"Johnson M.","family":"Moliki","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology University of Cape Town  Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0733-6837","authenticated-orcid":false,"given":"Sigcinile","family":"Dlamini","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology University of Cape Town  Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2421-7215","authenticated-orcid":false,"given":"Michele","family":"Tomasicchio","sequence":"additional","affiliation":[{"name":"Centre for Lung Infection and Immunity Division of Pulmonology Department of Medicine University of Cape Town and UCT Lung Institute  Cape Town South Africa"},{"name":"South African MRC Centre for the Study of Antimicrobial Resistance University of Cape Town  Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3080-1007","authenticated-orcid":false,"given":"G. 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