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Methyltransferase-like 3 (METTL3) is the principal catalytic enzyme responsible for m\n                      <jats:sup>6<\/jats:sup>\n                      A deposition, and its pharmacological inhibition has emerged as a potential therapeutic strategy for cancer and viral infections. However, the relative potency of METTL3 inhibitors in reducing m\n                      <jats:sup>6<\/jats:sup>\n                      A levels and their effects on HIV-1 latency reversal remain undefined. Here, we compared three commercially available METTL3 inhibitors (STM2457, STM3006, and STC-15) to evaluate their ability to reduce RNA m\n                      <jats:sup>6<\/jats:sup>\n                      A levels, suppress HIV-1 latency reversal, and affect cell viability in latently infected J-Lat cells and primary CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. In J-Lat cells, STM3006 and STC-15 were more potent than STM2457 in reducing RNA m\n                      <jats:sup>6<\/jats:sup>\n                      A levels at 24 and 48 h post-treatment, as reflected by lower half-maximal inhibitory concentrations (IC\n                      <jats:sub>50<\/jats:sub>\n                      ). However, STM3006 and STC-15 exhibited significant cytotoxicity at concentrations above 2 \u00b5M at 48 h post-treatment, whereas STM2457 displayed minimal toxicity across all tested doses. In primary CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells from three healthy donors, all three inhibitors reduced RNA m\n                      <jats:sup>6<\/jats:sup>\n                      A levels except STC-15 treatment of one donor\u2019s cells, while STM3006 induced significant cytotoxicity at 24 h post-treatment. Notably, reduced RNA m\n                      <jats:sup>6<\/jats:sup>\n                      A levels correlated with diminished HIV-1 latency reversal in both J-Lat cells and a primary central memory CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell model. Together, these findings demonstrate differential potency and cytotoxicity among METTL3 inhibitors and support a critical role for m\n                      <jats:sup>6<\/jats:sup>\n                      A RNA modification in regulating HIV-1 latency reversal.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00400-26","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T06:46:42Z","timestamp":1780037202000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Pharmacological METTL3 inhibition attenuates HIV-1 latency reversal in CD4\n                    <sup>+<\/sup>\n                    T cells"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0968-5654","authenticated-orcid":true,"given":"Tarun","family":"Mishra","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036jqmy94","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, Carver College of Medicine, The University of Iowa","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0869-686X","authenticated-orcid":true,"given":"Avary","family":"Edwards","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036jqmy94","id-type":"ROR","asserted-by":"publisher"}],"name":"Biomedical Sciences Graduate Program, Carver College of Medicine, University of Iowa","place":["Iowa City, 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