{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:50:45Z","timestamp":1787010645486,"version":"build-2736575974"},"posted":{"date-parts":[[2025,11,6]]},"group-title":"Immunology","reference-count":93,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["P20GM103629, R01DK131930, R56DK131531, P51OD011104, R01DK129881, R01HL165265, R01 HL141132, R01HL070241, 3R01HL070241-16S1, CTSA NCATS UM1TR004771, R01HL142796"],"award-info":[{"award-number":["P20GM103629, R01DK131930, R56DK131531, P51OD011104, R01DK129881, R01HL165265, R01 HL141132, R01HL070241, 3R01HL070241-16S1, CTSA NCATS UM1TR004771, R01HL142796"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) experience persistent inflammation, immune dysfunction, and premature onset of cardiovascular and aging-related comorbidities. To define the underlying mechanisms, we performed longitudinal transcriptomic profiling in peripheral blood mononuclear cells (PBMCs) from a cohort of simian immunodeficiency virus (SIV)-infected rhesus macaques spanning four key stages: pre-infection, acute infection, short-term ART, and long-term ART. Bulk RNA sequencing revealed dynamic immune remodeling across infection and treatment. Acute SIV infection induced robust antiviral and inflammatory programs, with upregulation of interferon-stimulated genes (ISGs), IL-27, JAK\/STAT, and NF-\u03baB signaling, coupled with suppression of T- and B-cell activation pathways. Short-term ART effectively reversed these transcriptional perturbations, restoring adaptive immune gene expression and reducing innate antiviral responses to near-baseline levels. In contrast, chronic SIV infection on long-term ART maintained viral suppression but was characterized by reactivation of innate immune pathways, including TLR2\/TLR4\/MYD88, NF-\u03baB, and inflammasome (NLRP3\/or NLRP12, caspase-1) signaling, along with sustained macrophage activation, platelet\/coagulation signaling, and senescence-associated secretory phenotype. Protein analyses confirmed persistent CASPASE-1 and NF-\u03baB activation in spleen tissue. Pathologic evaluation of a carotid artery from an SIV-infected, long-term ART\u2013 treated macaque revealed macrophage-rich plaques with p21\u207a senescent cells with intraluminal thrombus formation, recapitulating key features of HIV-associated atherogenesis. Together, these findings demonstrate that while ART normalizes acute infection\u2013induced immune dysregulation, chronic SIV infection sustains a chronic, macrophage- and TLR-driven inflammatory state linked to vascular injury and aging process regardless of long-term suppression of viremia. Targeting inflammasome, NF-\u03baB, and senescence pathways may mitigate non-AIDS comorbidities in PLWH.<\/jats:p>","DOI":"10.1101\/2025.11.05.686810","type":"posted-content","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T01:20:24Z","timestamp":1762478424000},"source":"Crossref","is-referenced-by-count":2,"title":["Persistent Activation of Monocytes\/Macrophages and Cell Senescence in SIV-Infected Macaques on ART"],"prefix":"10.64898","author":[{"given":"Yilin","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonalika","family":"Ray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siva","family":"Thirugnanam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Blair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Saied","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergiy","family":"Sukhanov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Kolls","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woong-Ki","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrice","family":"Delafontaine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Rappaport","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuebin","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0609-0767","authenticated-orcid":false,"given":"Namita","family":"Rout","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025111000250779000_2025.11.05.686810v1.1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.033369"},{"key":"2025111000250779000_2025.11.05.686810v1.2","doi-asserted-by":"publisher","DOI":"10.4084\/mjhid.2011.030"},{"issue":"2","key":"2025111000250779000_2025.11.05.686810v1.3","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1161\/ATVBAHA.122.318232","article-title":"Cardiovascular Disease and Thrombosis in HIV Infection. 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