{"doi":"10.1073/pnas.2309925121","title":"Vulnerability to APOBEC3G linked to the pathogenicity of deltaretroviruses","abstract":"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–lymphoma (ATL). We analyzed the proviral sequences of HTLV-1, HTLV-2, and simian T-cell leukemia virus type 1 (STLV-1) from Japanese macaques ( Macaca fuscata ) 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)-β/Smad pathway by HBZ, and this activation is associated with ATL cell proliferation by up-regulating BATF3/IRF4 and MYC . In contrast, the combination of APH-2 and hA3G, or the combination of SBZ and sA3G, does not enhance the TGF-β/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-β/Smad pathway. Antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis.","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":429870,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":639126,"name":"Jun‐ichirou Yasunaga","orcid":"0000-0002-7939-2080","position":1,"is_corresponding":false},{"id":37911,"name":"Kei Sato","orcid":"0000-0003-4431-1380","position":2,"is_corresponding":false},{"id":639125,"name":"Kisato Nosaka","orcid":"0000-0001-6682-2451","position":3,"is_corresponding":false},{"id":1232536,"name":"Kosuke Toyoda","orcid":"0000-0001-8125-4528","position":4,"is_corresponding":false},{"id":1012385,"name":"Miho Watanabe","orcid":"0009-0002-0764-2287","position":5,"is_corresponding":false},{"id":1232537,"name":"Wenyi Zhang","orcid":"0009-0006-9885-411X","position":6,"is_corresponding":false},{"id":979818,"name":"Yoshio Koyanagi","orcid":"0000-0002-3007-6642","position":7,"is_corresponding":false},{"id":447273,"name":"Edward L. Murphy","orcid":"0000-0001-6515-3989","position":8,"is_corresponding":false},{"id":324056,"name":"Roberta Bruhn","orcid":"0000-0002-5898-8168","position":9,"is_corresponding":false},{"id":1232892,"name":"Ki‐Ryang Koh","orcid":null,"position":10,"is_corresponding":false},{"id":1232538,"name":"Hirofumi Akari","orcid":"0000-0003-2166-6015","position":11,"is_corresponding":false},{"id":615281,"name":"Terumasa Ikeda","orcid":"0000-0003-2869-9450","position":12,"is_corresponding":false},{"id":257763,"name":"Reuben S. Harris","orcid":"0000-0002-9034-9112","position":13,"is_corresponding":false},{"id":411451,"name":"Patrick L. Green","orcid":"0000-0002-0204-562X","position":14,"is_corresponding":false},{"id":639152,"name":"Masao Matsuoka","orcid":"0000-0002-0473-754X","position":15,"is_corresponding":false},{"id":1232535,"name":"Takafumi Shichijo","orcid":"0000-0002-1272-3738","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T01:59:11.328802Z","pmid":"38502701","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}