{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:59:21Z","timestamp":1790780361238,"version":"4.1.0"},"reference-count":89,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/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. The mechanisms driving this transition from acute immune activation to chronic inflammatory remodeling under viral suppression remain incompletely understood. Here, we leveraged a nonhuman primate model to characterize the longitudinal transcriptomic changes across key stages of SIV infection and ART.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\/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\u2013treated macaque revealed macrophage-rich plaques with p21\u207a senescent cells with intraluminal thrombus formation, recapitulating key features of HIV-associated atherogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>While ART normalizes acute infection-induced 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>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1788994","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T06:48:37Z","timestamp":1773298117000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Persistent activation of monocytes\/macrophages and cell senescence in SIV-infected macaques on ART"],"prefix":"10.3389","volume":"17","author":[{"given":"Yilin","family":"Chen","sequence":"first","affiliation":[{"name":"Tulane National Biomedical Research Center, Tulane University","place":["Covington, LA, United States"]},{"name":"Department of Microbiology and Immunology, Tulane University School of Medicine","place":["New Orleans, LA, United 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