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Transl. Med."],"published-print":{"date-parts":[[2026,6,3]]},"abstract":"<jats:p>\n                    As the primary receptor for HIV-1 entry, human CD4 is widely recognized as the hallmark of HIV-1 target cells. However, viral negative factor (Nef) and viral protein U (Vpu) down-regulate surface CD4 on infected cells, raising an intriguing question: If an infected CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell survives and establishes latency, can CD4 expression recover? By tracking the fate of HIV-1\u2013infected CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, we unexpectedly found that a subset of these cells directly convert to CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. T cell receptor (TCR) sequencing and single-cell RNA sequencing data revealed that these induced CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells primarily originated from regulatory CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, which retained a regulatory-like phenotype postconversion. Mechanistically, HIV-1 viral protein R (Vpr) specifically induced this conversion by up-regulating transforming growth factor\u2013\u03b21 (TGF-\u03b21), which, in turn, activates a TGF-\u03b2\u2013dependent signaling pathway essential for CD8 lineage reprogramming. Critically, ex vivo analyses confirmed that CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells from both untreated and antiretroviral therapy (ART)\u2013suppressed people living with HIV-1 (PLWH) harbor transcriptionally active viral RNA or intact proviral DNA. Furthermore, we identified that human leukocyte antigen (HLA) class II\u2013restricted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, which were present in PLWH but absent in healthy controls, share TCR clonotypes with their antigen-specific CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell counterparts, providing direct evidence for HIV-1\u2013driven CD4-to-CD8 conversion in vivo. Collectively, these findings uncover a viral mechanism of host-cell reprogramming, demonstrate that CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells constitute a previously overlooked component of the HIV-1 reservoir, and broaden our understanding of latent reservoir heterogeneity, an essential consideration for future cure strategies.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.aec4912","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T17:59:12Z","timestamp":1780509552000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["HIV-1 infection converts CD4\n                    <sup>+<\/sup>\n                    T cells to HLA class II\u2013restricted CD8\n                    <sup>+<\/sup>\n                    T cells"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8356-030X","authenticated-orcid":true,"given":"Jinfeng","family":"Cai","sequence":"first","affiliation":[{"name":"Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China."},{"name":"Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2201-7164","authenticated-orcid":true,"given":"Wei","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Genetics and Biomedical Informatics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, 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