{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:59:14Z","timestamp":1775804354802,"version":"3.50.1"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006601","name":"Ministero degli Affari Esteri e della Cooperazione Internazionale","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Antiretroviral therapy (ART) suppresses HIV replication but fails to eradicate viral reservoirs or fully restore immune competence. Therapeutic vaccination targeting HIV-1 Tat, a key viral protein persistently expressed also during ART, may enhance immune reconstitution and limit reservoir maintenance. Long-term data in individuals infected with HIV-1 clade C, particularly in sub-Saharan Africa, are lacking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted a 12-year extended follow-up of 161 ART-treated adults previously enrolled in a randomized, placebo-controlled phase 2 trial of therapeutic HIV-1 Tat vaccination in South Africa (ISS T-003; SANCTR n. DOH-27-0211-3351; ClinicalTrials.gov: NCT01513135). No booster immunizations were administered. Longitudinal outcomes included anti-Tat antibody (Ab) persistence, CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell counts, plasma HIV RNA, and total HIV DNA in peripheral CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Analyses were stratified by sex and ART adherence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Ninety-seven percent of vaccinees developed anti-Tat Abs after immunization, and 70% were still positive at the beginning of the extended follow-up (3 years). Among these, 39% maintained Ab responses for their entire observation period (median duration 4 years), and 17 participants (20%) remained anti-Tat Ab seropositive up to year 12. Moreover, both Ab durability and peak titers were greater in vaccinees than in naturally occurring antibodies in seroconverter placebos. Compared with placebo, Tat vaccination was associated with earlier and sustained CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell recovery and accelerated decline of total HIV DNA, effects that persisted for more than a decade. These benefits were most pronounced in men, who were more immunocompromised at baseline, and in individuals with suboptimal ART adherence. Notably, vaccinated participants with intermittent viremia maintained stable or increasing CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell counts and continued reservoir reduction over time.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Therapeutic HIV-1 Tat vaccination induces long-lasting immunological benefits that extend beyond viral suppression achieved by ART alone, promoting durable immune reconstitution and progressive reservoir decay in clade C infection. These findings confirm results from a long-term follow-up of a parallel phase 2 trial in Italy, and both support Tat vaccination as a potential ART-intensifying strategy, particularly in populations with advanced immunosuppression or imperfect ART adherence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>SANCTR n. DOH-27-0615\u20134948 and ClinicalTrials.gov: NCT02712489; and SANCTR n. DOH-27-072022\u20137347 and ClinicalTrials.gov: NCT05680948.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1769223","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:04:00Z","timestamp":1775801040000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic HIV-1 Tat vaccination promotes durable immune reconstitution and reservoir reduction in ART-treated adults with clade C infection: a 12-year follow-up study"],"prefix":"10.3389","volume":"17","author":[{"given":"Orietta","family":"Picconi","sequence":"first","affiliation":[{"name":"National HIV\/AIDS Research Center, Istituto Superiore di Sanit\u00e0","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecilia","family":"Sgadari","sequence":"additional","affiliation":[{"name":"National HIV\/AIDS Research Center, Istituto Superiore di 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