{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:25:59Z","timestamp":1785432359102,"version":"3.56.0"},"reference-count":59,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["FDN-154324,HB2-164064"],"award-info":[{"award-number":["FDN-154324,HB2-164064"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2025,12,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      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\n                      <jats:italic toggle=\"yes\">MARCH1<\/jats:italic>\n                      RNA. Mechanistically, Vpu interaction with the \u03b2-TrCP substrate receptor of the SCF\n                      <jats:sup>\u03b2-TrCP<\/jats:sup>\n                      E3 ligase, a host partner critical for Vpu functions, leads to a stabilization of SCF\n                      <jats:sup>\u03b2-TrCP<\/jats:sup>\n                      cellular targets, such as \u03b2-catenin, which drives transcription of the\n                      <jats:italic toggle=\"yes\">MARCH1<\/jats:italic>\n                      -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\n                      <jats:italic toggle=\"yes\">MARCH1<\/jats:italic>\n                      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 \u03b2-TrCP-1 and 2 or pharmacological inhibition of \u03b2-catenin in THP-1 cells revealed that Env-mediated upregulation of microRNA 25 and 93 is \u03b2-TrCP dependent and involves \u03b2-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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic toggle=\"yes\">vpu<\/jats:italic>\n                      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 \u03b2-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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01663-25","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T14:00:19Z","timestamp":1763992819000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["HIV-2 glycoproteins upregulate microRNAs 25 and 93 to counter the MARCH1 antiviral effect in macrophages"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9908-0850","authenticated-orcid":false,"given":"Robert","family":"Lodge","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05m8pzq90","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Human 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