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We investigated whether cannabinoid receptor 2 (CB<jats:sub>2<\/jats:sub>), an immunomodulatory receptor expressed in myeloid cells, regulates viral replication and inflammation in HIV-infected macrophages and microglia. Using the synthetic CB<jats:sub>2<\/jats:sub>-specific agonist JWH-133, we found that CB<jats:sub>2<\/jats:sub> activation reduced HIV replication in primary human monocyte-derived macrophages (MDMs) and human induced pluripotent stem cell-derived microglia (iMg) at differing doses, corresponding to the basal expression of <jats:italic>CNR2<\/jats:italic>, which encodes CB<jats:sub>2<\/jats:sub>, and related endocannabinoid transcripts in each cell type. JWH-133 broadly reduced release of cytokines from HIV-infected MDMs but not iMg. RNA-seq revealed that CB<jats:sub>2<\/jats:sub> agonism primarily altered interferon and integrated stress response pathways in MDMs while altering homeostatic pathways, including synapse maintenance and phagocytosis, in iMg. Further analyses in iMg revealed that NLRP3 inflammasome activation, but not priming, was reduced by CB<jats:sub>2<\/jats:sub> activation, which did not inhibit HIV-induced nuclear factor kB activation. This study identifies key differences in CB<jats:sub>2<\/jats:sub> response between myeloid lineage cell types and implicates CB<jats:sub>2<\/jats:sub>-specific agonists as promising candidates for the regulation of HIV-associated neuroinflammation.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical Abstract<\/jats:bold>\n          <\/jats:p>\n          <jats:p>Created in BioRender. Espinoza, C. (2025) <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/BioRender.com\/mxfla3i\" ext-link-type=\"uri\">https:\/\/BioRender.com\/mxfla3i<\/jats:ext-link>\n          <\/jats:p>","DOI":"10.1007\/s11481-025-10254-x","type":"journal-article","created":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:21:28Z","timestamp":1760163688000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Differential Effects of Cannabinoid Receptor 2 Agonists on HIV Replication and Inflammatory Activation in Monocyte-Derived Macrophages and Induced Pluripotent Stem Cell-Derived Microglia"],"prefix":"10.1007","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0756-4082","authenticated-orcid":false,"given":"Alexander","family":"Starr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Rathore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7703-8777","authenticated-orcid":false,"given":"Marzieh","family":"Daniali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0095-5424","authenticated-orcid":false,"given":"Peter J.","family":"Gaskill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0199-3836","authenticated-orcid":false,"given":"Cagla","family":"Akay-Espinoza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0827-1337","authenticated-orcid":false,"given":"Kelly L.","family":"Jordan-Sciutto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,11]]},"reference":[{"key":"10254_CR1","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.3389\/fmicb.2015.01452","volume":"6","author":"M Agudelo","year":"2015","unstructured":"Agudelo M, Figueroa G, Yndart A, Casteleiro G, Mu\u00f1oz K, Samikkannu T, Atluri V, Nair MP (2015) Alcohol and cannabinoids differentially affect HIV infection and function of human monocyte-derived dendritic cells (MDDC). 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