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This reservoir is thought to form by initial infection of antigen-activated CD4+ T-cells that then transition into quiescent memory CD4+ T cells. However, na\u00efve CD4+ T cells have been shown to harbor integrated HIV-1 in adults with non-perinatally acquired HIV-1, and more recently in young children. Given that perinatal HIV-1 transmission is established in an immune environment dominated by na\u00efve CD4+ T cells, we hypothesized that na\u00efve CD4+ T cells may be a substantial reservoir in young adults with longstanding perinatal infection. To investigate this, we studied a cohort of 10 adolescents and young adults (AYA) living with well-controlled, perinatally-acquired HIV-1. We quantified and characterized intact and defective HIV-1 proviruses and their location in sorted na\u00efve and memory CD4+ T cells using an intact proviral DNA assay, near full-length single genome sequencing, and integration site profiling. We found that a median of 93.5% of HIV-1 proviruses resided in memory CD4+ T cells in AYA with perinatal HIV-1, with a few participants also having intact proviruses in na\u00efve CD4+ T cells, but at substantially lower frequencies. HIV-1 integration site analysis, using the unbiased ligation-mediated PCR method, showed that 78.0% of proviruses were located within active transcription units in introns and 46.9% of integration sites were clonal, with detection in multiple cells. Overall, similar to adults with non-perinatally acquired HIV-1, integration sites were enriched in regions with epigenetic marks for active enhancers and transcription. Therapies to attain HIV-1 ART-free remission and cure for this population will need to consider reservoirs in non-canonical T cells subsets, as well as substantial HIV-1 infected cells arising from cellular proliferation.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014369","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T17:37:34Z","timestamp":1783964254000},"page":"e1014369","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quantification and localization of integrated HIV-1 in memory and na\u00efve CD4+ T cells from adolescents and young adults with perinatally-acquired HIV-1"],"prefix":"10.1371","volume":"22","author":[{"given":"Adit","family":"Dhummakupt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G.","family":"McFarland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Szewczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Everett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoife M.","family":"Roche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumia","family":"Bekka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuy","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison L.","family":"Agwu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic D.","family":"Bushman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Persaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"issue":"5","key":"ppat.1014369.ref001","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/8394","article-title":"Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy","volume":"5","author":"D Finzi","year":"1999","journal-title":"Nat Med"},{"issue":"7","key":"ppat.1014369.ref002","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1172\/JCI9006","article-title":"A stable latent reservoir for HIV-1 in resting CD4(+) T lymphocytes in 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