{"doi":"10.1128/jvi.01870-22","title":"HIV-2 inhibits HIV-1 gene expression via two independent mechanisms during cellular co-infection","abstract":"ABSTRACT Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). The two main forms of HIV are HIV-1 and HIV-2; in the clinic, each is predominantly found in the context of monoinfection. However, dual infections are found in regions where HIV-1 and HIV-2 coexist, such as West Africa. Both viruses can induce AIDS; however, HIV-2 is generally less pathogenic than HIV-1 and progresses more slowly to AIDS. Additionally, there are reports that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, and in cell culture. However, the mechanisms underlying these protective effects are not well understood. To decipher these mechanisms, we performed dual infections with HIV-1 and HIV-2 in cell culture. We demonstrated that HIV-1 and HIV-2 can co-infect individual cells. HIV-2 infection was found to inhibit HIV-1 infection when performed prior to or simultaneously with HIV-1 infection. Two distinct mechanisms were identified. First, HIV-2 induces an interferon (IFN) response that broadly inhibits gene expression. Second, in the absence of IFN production, HIV-1-specific inhibition was found to be conferred by the HIV-2 trans-activation response (TAR) element. The HIV-2 TAR (TAR-2) element appears to inhibit HIV-1 long terminal repeat (LTR) promoter activity through competition with the HIV-1 TAR element for HIV-1 Tat binding. We show that this results in suppression of HIV-1 LTR-driven transcription by stalling RNA polymerase II early transcription complexes at the HIV-1 LTR promoter region. IMPORTANCE Twenty-five years after the first report that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, the mechanisms are still not well understood. We explored these mechanisms in cell culture and showed first that these viruses can co-infect individual cells. Under specific conditions, HIV-2 inhibits HIV-1 through two distinct mechanisms, a broad-spectrum interferon response and an HIV-1-specific inhibition conferred by the HIV-2 TAR. The former could play a prominent role in dually infected individuals, whereas the latter targets HIV-1 promoter activity through competition for HIV-1 Tat binding when the same target cell is dually infected. That mechanism suppresses HIV-1 transcription by stalling RNA polymerase II complexes at the promoter through a minimal inhibitory region within the HIV-2 TAR. This work delineates the sequence of appearance and the modus operandi of each mechanism.","journal":"Journal of Virology","year":2023,"id":366420,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":465091,"name":"Kinjal Majumder","orcid":"0000-0002-1898-8251","position":1,"is_corresponding":false},{"id":253447,"name":"Philip R. Tedbury","orcid":"0000-0001-8151-4967","position":2,"is_corresponding":false},{"id":1122633,"name":"Xin Wen","orcid":"0000-0003-4762-7567","position":3,"is_corresponding":false},{"id":693448,"name":"Yee Tsuey Ong","orcid":"0000-0001-9361-2855","position":4,"is_corresponding":false},{"id":347974,"name":"Marc C. Johnson","orcid":"0000-0002-6431-7133","position":5,"is_corresponding":false},{"id":253448,"name":"Stefan G. Sarafianos","orcid":"0000-0002-5840-154X","position":6,"is_corresponding":false},{"id":1122632,"name":"Vincent Yapo","orcid":"0009-0002-8829-6880","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:14:55.198227Z","pmid":"37991365","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":[]}