{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T15:28:42Z","timestamp":1776439722491,"version":"3.51.2"},"reference-count":84,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health National Institute of General Medical Sciences (NIGMS) PR-INBRE-Institutional Developmental Award","award":["P20GM103475"],"award-info":[{"award-number":["P20GM103475"]}]},{"name":"Research Infrastructure Core Components\u2014National Institute of Minority Health and Health Disparities","award":["U54MD007600"],"award-info":[{"award-number":["U54MD007600"]}]},{"name":"Translational Proteomics Center","award":["F99NS11345"],"award-info":[{"award-number":["F99NS11345"]}]},{"name":"Translational Proteomics Center","award":["K00NS11345"],"award-info":[{"award-number":["K00NS11345"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health","award":["R25DK113659"],"award-info":[{"award-number":["R25DK113659"]}]},{"name":"Comprehensive Cancer Center of the UPR"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although antiviral therapy has improved quality of life, around 50% of people with HIV (PWH) experience neurodegeneration and cognitive decline. This is prompted in part by the migration of HIV-infected monocyte-derived macrophages (MDMs) to the brain, leading to neuronal death. Previous studies in our lab have shown that HIV-infected MDMs secrete cathepsin B (CATB), which is a pro-inflammatory neurotoxic enzyme that is reduced by the addition of cannabinoid receptor-2 (CB2R) agonist JWH-133 to cell cultures. In this study, we aimed to identify the proteins secreted (secretome) by HIV-infected macrophages exposed to JWH-133 and quantify them using tandem mass tag (TMT) mass spectrometry. Frozen 13-day MDM supernatants from (1) an MDM negative control; (2) HIV+MDM, and (3) HIV+MDM-JWH-133 were compared in triplicate by mass spectrometry (LC\/MS\/MS) and analyzed for protein identification. Subsequently, the same samples were labeled by TMT labeling and quantified by LC\/MS\/MS. After a database search, 528 proteins were identified from all groups. Thereafter, proteins with more than three unique peptides and more than 10% coverage were selected for protein identification. Venn diagrams revealed one unique protein secreted by MDM-HIV, 10 unique proteins in HIV+MDM-JWH-133, and 15 common proteins in the three groups. CATB was unique to HIV+MDM. HIV+MDM exposed to JWH-133 showed proteins related to metabolism, cell organization, antiviral activity, and stress response. TMT analysis revealed 1454 proteins with abundance for statistical analysis based on FC \u2265 |1.5| and p-value \u2264 0.05, of which Ruvb-like 1 and Hornerin decreased significantly with JWH-133 treatment. Both proteins stimulate HIV replication. In addition, HIV infection upregulated proteins associated with pathways of viral latency that were inhibited by JWH-133. In conclusion, JWH-133 treatment in HIV-infected macrophages leads to the secretion of antiviral host factors and decreases the secretion of proviral, inflammatory, and neurotoxic host factors.<\/jats:p>","DOI":"10.3390\/ijms262110596","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T01:23:59Z","timestamp":1761873839000},"page":"10596","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Cannabinoid Receptor Type 2 Agonist JWH-133 Stimulates Antiviral Factors and Decreases Proviral, Inflammatory, and Neurotoxic Proteins in HIV-Infected Macrophage Secretome"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1004-152X","authenticated-orcid":false,"given":"Lester J.","family":"Rosario-Rodr\u00edguez","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yadira M.","family":"Cantres-Rosario","sequence":"additional","affiliation":[{"name":"Translational Proteomics Center, Research Capacity Core, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana E.","family":"Rodr\u00edguez De Jes\u00fas","sequence":"additional","affiliation":[{"name":"Translational Proteomics Center, Research Capacity Core, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alana M.","family":"Mera-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Puerto Rico-R\u00edo Piedras Campus, San Juan, PR 00925, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9140-8671","authenticated-orcid":false,"given":"Eduardo L.","family":"Tosado-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Integrated Informatics Services, Research Capacity Core, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"},{"name":"School of Dental Medicine, Universidad Ana G. M\u00e9ndez, Gurabo, PR 00778, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2246-6744","authenticated-orcid":false,"given":"Abiel","family":"Roche Lima","sequence":"additional","affiliation":[{"name":"Integrated Informatics Services, Research Capacity Core, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2571-8206","authenticated-orcid":false,"given":"Loyda M.","family":"Mel\u00e9ndez","sequence":"additional","affiliation":[{"name":"Translational Proteomics Center, Research Capacity Core, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"},{"name":"Department of Microbiology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"ref_1","unstructured":"(2025). 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