Distinct phases of immune system programming during ART-suppressed immunodeficiency virus infection
People living with HIV (PLWH) on suppressive antiretroviral therapy (ART) can face non-AIDS complications, partially driven by chronic immune activation. 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-β and NF-κB 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.
Authors
- Jacob D. Estes (ORCID: https://orcid.org/0000-0002-9652-6394)
- Sebastián Benjamín
- Karina Belica (ORCID: https://orcid.org/0009-0001-5925-3657)
- Morgan Chaunzwa (ORCID: https://orcid.org/0000-0003-3062-0422)
- Andrea N. Selseth (ORCID: https://orcid.org/0000-0001-9536-463X)
- Benjamin N. Bimber (ORCID: https://orcid.org/0000-0001-8092-3080)
- Gregory J. Boggy (ORCID: https://orcid.org/0000-0002-8283-5620)
- Louis J. Picker (ORCID: https://orcid.org/0000-0003-0546-398X)
- Sohita Ojha (ORCID: https://orcid.org/0009-0008-4473-7078)
- Shana Feltham (ORCID: https://orcid.org/0009-0004-5862-5860)
- Maanasa Kaza (ORCID: https://orcid.org/0009-0000-4278-9108)
- GW McElfresh
- Brandon F Keele (ORCID: https://orcid.org/0000-0002-2381-1151)
- Jeffrey D. Lifson (ORCID: https://orcid.org/0000-0002-9494-0268)
- Kathleen Busman-Sahay (ORCID: https://orcid.org/0000-0002-8549-0023)
- Michael Nekorchuk
- Dan H. Barouch (ORCID: https://orcid.org/0000-0001-5127-4659)
- Scott G. Hansen (ORCID: https://orcid.org/0000-0002-9845-6481)
- Benjamin Varco-Merth
- Afam Okoye (ORCID: https://orcid.org/0000-0001-9671-550X)
Institutions
- Oregon National Primate Research Center (US)
- Beth Israel Deaconess Medical Center (US)
- Oregon Health & Science University (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Frederick National Laboratory for Cancer Research (US)
- Children's Cancer Therapy Development Institute (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-05-01
- DOI
- https://doi.org/10.64898/2026.04.29.721702
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health