Distinct phases of immune system programming during ART-suppressed immunodeficiency virus infection

Kaza, M.; Varco-Merth, B.; McElfresh, G.; Benjamin, S.; Boggy, G. J.; Chaunzwa, M.; Feltham, S.; Ojha, S.; Belica, K.; Selseth, A. N.; Nekorchuk, M.; Busman-Sahay, K.; Keele, B. F.; Barouch, D. H.; Lifson, J. D.; Estes, J. D.; Hansen, S. G.; Okoye, A.; Picker, L. J.; Bimber, B. N.

doi:10.64898/2026.04.29.721702

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bioRxiv · 10.64898/2026.04.29.721702

Distinct phases of immune system programming during ART-suppressed immunodeficiency virus infection

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Abstract

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-{beta} 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.

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Kaza, M., Varco-Merth, B., McElfresh, G., Benjamin, S., Boggy, G. J., Chaunzwa, M., Feltham, S., Ojha, S., Belica, K., Selseth, A. N., Nekorchuk, M., Busman-Sahay, K., Keele, B. F., Barouch, D. H., Lifson, J. D., Estes, J. D., Hansen, S. G., Okoye, A., Picker, L. J., Bimber, B. N.. 2026-05-01. Distinct phases of immune system programming during ART-suppressed immunodeficiency virus infection. https://doi.org/10.64898/2026.04.29.721702

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