{"doi":"10.1093/nar/gkaf826","title":"HIV-2 evades restriction by ZAP through adaptations in the U3 LTR region despite increased CpG levels","abstract":"Simian immunodeficiency viruses infecting sooty mangabeys (SIVsmm) gave rise to nine groups of human immunodeficiency virus type 2 (HIV-2). Two of these (A and B) spread substantially with an estimated 1-2 million individuals affected. The evolutionary adaptations that facilitated HIV-2's spread in humans are still poorly understood. Here, we report that diverse SIVsmm strains efficiently infect primary human T cells. However, they are more sensitive to interferon than HIV-2, indicating that interferon-stimulated genes (ISGs) pose a barrier to the successful spread of SIVsmm in humans. One of the best-known antiviral ISGs is the zinc finger antiviral protein (ZAP), which targets CpG dinucleotides in RNA. To evade ZAP-mediated restriction, many viruses, including HIV-1, suppress their CpG content. Unexpectedly, we found that HIV-2 is more resistant to ZAP restriction than HIV-1 and SIVsmm despite having 33% more CpGs. Identification of ZAP-binding sites using RNA enhanced crosslinking immunoprecipitation and analyses of chimeric HIV-2/SIVsmm viruses revealed that the determinants of ZAP resistance map to the nef/U3 region and promote HIV-2 replication in primary human T cells. Our results indicate that HIV-2 evolved a CpG-independent ZAP resistance mechanism which might have been facilitated by relaxed functional constraints acting on Nef in the human host.","journal":"Nucleic Acids Research","year":2025,"id":573760,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":576032,"name":"Rayhane Nchioua","orcid":"0009-0001-1436-1232","position":1,"is_corresponding":false},{"id":1030528,"name":"Alexander Gabel","orcid":"0000-0002-8064-3289","position":2,"is_corresponding":false},{"id":1481290,"name":"Asimenia Vlachou","orcid":null,"position":3,"is_corresponding":false},{"id":1030526,"name":"Sabina Ganskih","orcid":"0000-0002-1710-1014","position":4,"is_corresponding":false},{"id":631451,"name":"Sümeyye Erdemci-Evin","orcid":null,"position":5,"is_corresponding":false},{"id":709070,"name":"Stacey A. Lapp","orcid":"0000-0002-6887-7322","position":6,"is_corresponding":false},{"id":247221,"name":"Diane G. Carnathan","orcid":"0009-0001-7073-3723","position":7,"is_corresponding":false},{"id":232942,"name":"Steven E. Bosinger","orcid":"0000-0002-2116-5061","position":8,"is_corresponding":false},{"id":277331,"name":"Ben Berkhout","orcid":"0000-0002-1905-8486","position":9,"is_corresponding":false},{"id":277329,"name":"Atze T. Das","orcid":"0000-0001-7891-2315","position":10,"is_corresponding":false},{"id":17152,"name":"Mathias Munschauer","orcid":"0000-0001-6143-4548","position":11,"is_corresponding":false},{"id":350334,"name":"Frank Kirchhoff","orcid":"0000-0002-7052-2360","position":12,"is_corresponding":false},{"id":576033,"name":"Dorota Kmieć","orcid":"0000-0001-7302-6015","position":0,"is_corresponding":true}],"reference_count":104,"raw_metadata":null,"created_at":"2026-07-19T02:57:36.753600Z","pmid":"40884399","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":[]}