{"doi":"10.1128/jvi.01663-25","title":"HIV-2 glycoproteins upregulate microRNAs 25 and 93 to counter the MARCH1 antiviral effect in macrophages","abstract":"ABSTRACT The membrane-associated E3 ubiquitin ligase MARCH1 restricts HIV-1 infectivity by decreasing the amount of cell surface Env glycoproteins and their incorporation into progeny virions. To circumvent this restriction, the HIV-1 accessory protein Vpu increases the levels of microRNAs 25 and 93 that target MARCH1 RNA. Mechanistically, Vpu interaction with the β-TrCP substrate receptor of the SCF β-TrCP E3 ligase, a host partner critical for Vpu functions, leads to a stabilization of SCF β-TrCP cellular targets, such as β-catenin, which drives transcription of the MARCH1 -targeting microRNAs. Here, we show that HIV-2 and SIVmac239, which do not encode for Vpu, also upregulate microRNAs 25 and 93 in macrophages, as well as in the macrophage-like THP-1 cell line model. Inhibiting the MARCH1 mRNA-targeting microRNAs impaired HIV-2 infectivity and reduced viral spread in macrophages. While none of the HIV-2 accessory proteins upregulated microRNAs 25 and 93, the Env glycoproteins of HIV-2 and SIVmac239 were sufficient to induce their expression. Depletion of β-TrCP-1 and 2 or pharmacological inhibition of β-catenin in THP-1 cells revealed that Env-mediated upregulation of microRNA 25 and 93 is β-TrCP dependent and involves β-catenin, similar to Vpu. Our findings highlight a new function of the HIV-2 and SIVmac239 glycoproteins as inducers of microRNAs 25 and 93 that counteract MARCH1 and potentiate viral replication in macrophages. IMPORTANCE Macrophage infection by primate lentiviruses (HIV-1, HIV-2, and SIV) is restricted by, among other host factors, the MARCH1 membrane-associated protein. HIV-1 circumvents the MARCH1 restriction by using its accessory protein Vpu, which induces the anti-MARCH1 microRNAs 25 and 93. HIV-2 has infected up to 2 million people so far, and SIV infection is indispensable for animal models of primate lentivirus pathogenesis. These two lentiviruses do not have a vpu gene, but also target MARCH1 by inducing the same microRNAs. We have now determined that the HIV-2 and SIV antagonists of MARCH1 are their envelope glycoproteins. The HIV-2 and SIVmac239 Env glycoproteins upregulate microRNAs 25 and 93 by disrupting the β-catenin pathway, similar to HIV-1 Vpu. The fact that different lentiviruses have developed a similar strategy using microRNAs to counter MARCH1 antiviral activity emphasizes its relevance in the antiviral host response, as well as a target in antiviral therapy.","journal":"Journal of Virology","year":2025,"id":582996,"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":0.9514,"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":576033,"name":"Dorota Kmieć","orcid":"0000-0001-7302-6015","position":1,"is_corresponding":false},{"id":350334,"name":"Frank Kirchhoff","orcid":"0000-0002-7052-2360","position":2,"is_corresponding":false},{"id":689257,"name":"Eric A. Cohen","orcid":"0000-0003-1269-3791","position":3,"is_corresponding":false},{"id":1113462,"name":"Robert Lodge","orcid":"0000-0002-9908-0850","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T02:58:59.653747Z","pmid":"41283654","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":[]}