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Extracellular vesicles (EVs) constitute a relatively uncharacterized modality of intercellular communication and bioactive cargo transport in the setting of viral infection and pathogenesis. EVs carry inflammatory mediators to areas of the periphery during antiretroviral therapy (ART) suppression but are understudied in the brain. Using a biologically relevant simian\u2013human immunodeficiency chimeric virus with a clade D HIV envelope (SHIV.D)-infected rhesus macaque (RM) model of HIV persistence in the central nervous system (CNS), we investigate circulating EV populations and the protein cargo of myeloid-derived EVs during SHIV infection. Using EV flow cytometry to quantify specific EV subpopulations, we found a significant increase in TMEM119+ microglial EVs and CD171+ neuronal EVs in RM plasma during viremia and ART suppression. Using primary RM monocyte-derived macrophages (MDMs), we determined that MDMs increased EV production after SHIV infection. Whole proteomic analysis of these EVs demonstrated that myeloid EVs isolated from SHIV.D-infected MDMs carried significantly increased levels of neuropathogenic and inflammatory proteins. Altogether, these studies improve our understanding of the contribution of myeloid EVs to neurological disease during SHIV\/HIV infection.<\/jats:p>","DOI":"10.3390\/ijms27020966","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T11:27:58Z","timestamp":1768908478000},"page":"966","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SHIV.D Infection Alters Production and Protein Composition of Myeloid-Derived Extracellular Vesicles"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1467-0921","authenticated-orcid":false,"given":"Rachel M.","family":"Podgorski","sequence":"first","affiliation":[{"name":"Center for NeuroVirology and Gene Editing, Department of Microbiology, Immunology, and Inflammation, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amir","family":"Yarmahmoodi","sequence":"additional","affiliation":[{"name":"Flow Cytometry Core Facility, Department of Microbiology, Immunology, and Inflammation, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2285-7676","authenticated-orcid":false,"given":"Stephen","family":"Baak","sequence":"additional","affiliation":[{"name":"Center for NeuroVirology and Gene Editing, Department of Microbiology, Immunology, and Inflammation, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Warfield","sequence":"additional","affiliation":[{"name":"Center for NeuroVirology and Gene Editing, Department of Microbiology, Immunology, and Inflammation, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jake A.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3852-1330","authenticated-orcid":false,"given":"Jennifer","family":"Roof","sequence":"additional","affiliation":[{"name":"Proteomics Core Facility, Children\u2019s Hospital of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio","family":"Caocci","sequence":"additional","affiliation":[{"name":"Department of Medicine, Rutgers Institute of Translational Medicine and Science, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hossein","family":"Fazelinia","sequence":"additional","affiliation":[{"name":"Proteomics Core Facility, Children\u2019s Hospital of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynn A.","family":"Spruce","sequence":"additional","affiliation":[{"name":"Proteomics Core Facility, Children\u2019s Hospital of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharine J.","family":"Bar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4224-7381","authenticated-orcid":false,"given":"Tricia H.","family":"Burdo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Rutgers Institute of Translational Medicine and Science, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nrm.2017.125","article-title":"Shedding light on the cell biology of extracellular vesicles","volume":"19","author":"Raposo","year":"2018","journal-title":"Nat. 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