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Methylation of the proviral 5\u2032 long terminal repeat (LTR) promoter region has been proposed as a possible mechanism contributing to HIV latency; however, conflicting observations exist regarding its relevance. We assessed 5\u2032-LTR methylation profiles in total CD4<jats:sup>+<\/jats:sup>T cells from blood of 12 participants on short-term ART (30 months) followed up for 2 years, and a cross-sectional group of participants with long-term ART (6\u201315 years), using next generation sequencing. We then looked for associations between specific 5\u2032-LTR methylation patterns and baseline and follow-up clinical characteristics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>5\u2032-LTR methylation was observed in all participants and behaved dynamically. The number of 5\u2032-LTR variants found per sample ranged from 1 to 13, with median sequencing depth of 16270\u00d7 (IQR 4107\u00d7-46760\u00d7). An overall significant 5\u2032-LTR methylation increase was observed at month 42 compared to month 30 (median CpG Methylation Index: 74.7% vs. 0%,<jats:italic>p<\/jats:italic>= 0.025). This methylation increase was evident in a subset of participants (methylation increase group), while the rest maintained fairly high and constant methylation (constant methylation group). Persons in the methylation increase group were younger, had higher CD4<jats:sup>+<\/jats:sup>T cell gain, larger CD8% decrease, and larger CD4\/CD8 ratio change after 48 months on ART (all<jats:italic>p<\/jats:italic>&lt; 0.001). Using principal component analysis, the constant methylation and methylation increase groups showed low evidence of separation along time (factor 2:<jats:italic>p<\/jats:italic>= 0.04). Variance was largely explained (21%) by age, CD4<jats:sup>+<\/jats:sup>\/CD8<jats:sup>+<\/jats:sup>T cell change, and CD4<jats:sup>+<\/jats:sup>T cell subpopulation proportions. Persons with long-term ART showed overall high methylation (median CpG Methylation Index: 78%; IQR 71\u201387%). No differences were observed in residual plasma viral load or proviral load comparing individuals on short-term (both at 30 or 42 months) and long-term ART.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study shows evidence that HIV 5\u2032-LTR methylation in total CD4+ T cells is dynamic along time and that it can follow different temporal patterns that are associated with a combination of baseline and follow-up clinical characteristics. These observations may account for differences observed between previous contrasting studies.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s13148-019-0735-9","type":"journal-article","created":{"date-parts":[[2019,9,13]],"date-time":"2019-09-13T04:39:46Z","timestamp":1568349586000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Longitudinal variation in human immunodeficiency virus long terminal repeat methylation in individuals on suppressive antiretroviral therapy"],"prefix":"10.1186","volume":"11","author":[{"given":"C\u00e9sar N.","family":"Cort\u00e9s-Rubio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"Salgado-Montes de Oca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Prado-Galbarro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarita","family":"Mat\u00edas-Florentino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Murakami-Ogasawara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"Kuri-Cervantes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana P.","family":"Carranco-Arenas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher E.","family":"Ormsby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivette K.","family":"Cort\u00e9s-Rubio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Reyes-Ter\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3371-4248","authenticated-orcid":false,"given":"Santiago","family":"\u00c1vila-R\u00edos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,9,13]]},"reference":[{"key":"735_CR1","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1097\/COH.0000000000000003","volume":"8","author":"C Flexner","year":"2013","unstructured":"Flexner C, Plumley B, Brown Ripin DH. 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