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To define immune perturbations during ART-suppressed viral infection, we performed longitudinal single-cell transcriptomic and plasma proteomic analysis of rhesus macaques infected with SIVmac239M and ART-treated for 70 weeks. We identified broad, bi-phasic immune changes. Acute infection involves an interferon-driven signature, correlated with viral replication, that largely resolves with viral control. Cell-associated virus correlated with interferon-stimulated genes in most tissues; however, this was blunted in gut-associated lymph nodes, a feature that may contribute to reservoir persistence. Separate alterations manifest 54-66 weeks-post-infection, after 40 weeks of viral suppression, including broad TGF-\u03b2 and NF-kB signaling and discrete bursts of inflammatory monocytes, largely restricted to bone marrow. These data highlight the biphasic remodeling of long-term ART-suppressed HIV, identifying specific tissues and cell populations with dysregulation, with implications for the treatment of PLWH.<\/jats:p>","DOI":"10.64898\/2026.04.29.721702","type":"posted-content","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T23:55:15Z","timestamp":1777679715000},"source":"Crossref","is-referenced-by-count":0,"title":["Distinct phases of immune system programming during ART-suppressed immunodeficiency virus infection"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4278-9108","authenticated-orcid":false,"given":"Maanasa","family":"Kaza","sequence":"first","affiliation":[{"name":"Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, 97006, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Varco-Merth","sequence":"additional","affiliation":[{"name":"Vaccine and Gene Therapy Institute, 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