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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,3,26]]},"abstract":"<jats:p>\n                    Human retroviruses are derived from simian ones through cross-species transmission. These retroviruses are associated with little pathogenicity in their natural hosts, but in humans, HIV causes AIDS, and human T-cell leukemia virus type 1 (HTLV-1) induces adult T-cell leukemia\u2013lymphoma (ATL). We analyzed the proviral sequences of HTLV-1, HTLV-2, and simian T-cell leukemia virus type 1 (STLV-1) from Japanese macaques (\n                    <jats:italic>Macaca fuscata<\/jats:italic>\n                    ) and found that APOBEC3G (A3G) frequently generates G-to-A mutations in the HTLV-1 provirus, whereas such mutations are rare in the HTLV-2 and STLV-1 proviruses. Therefore, we investigated the mechanism of how HTLV-2 is resistant to human A3G (hA3G). HTLV-1, HTLV-2, and STLV-1 encode the so-called antisense proteins, HTLV-1 bZIP factor (HBZ), Antisense protein of HTLV-2 (APH-2), and STLV-1 bZIP factor (SBZ), respectively. APH-2 efficiently inhibits the deaminase activity of both hA3G and simian A3G (sA3G). HBZ and SBZ strongly suppress sA3G activity but only weakly inhibit hA3G, suggesting that HTLV-1 is incompletely adapted to humans. Unexpectedly, hA3G augments the activation of the transforming growth factor (TGF)-\u03b2\/Smad pathway by HBZ, and this activation is associated with ATL cell proliferation by up-regulating\n                    <jats:italic>BATF3\/IRF4<\/jats:italic>\n                    and\n                    <jats:italic>MYC<\/jats:italic>\n                    . In contrast, the combination of APH-2 and hA3G, or the combination of SBZ and sA3G, does not enhance the TGF-\u03b2\/Smad pathway. Thus, HTLV-1 is vulnerable to hA3G but utilizes it to promote the proliferation of infected cells via the activation of the TGF-\u03b2\/Smad pathway. Antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2309925121","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T13:39:20Z","timestamp":1710855560000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["Vulnerability to APOBEC3G linked to the pathogenicity of deltaretroviruses"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1272-3738","authenticated-orcid":false,"given":"Takafumi","family":"Shichijo","sequence":"first","affiliation":[{"name":"Department of Hematology, Rheumatology and Infectious Diseases, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan"},{"name":"Laboratory of Virus Control, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, 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