Authors
Chen, Y., Ding, X., Ray, S., Thirugnanam, S., Blair, R., Saied, A., Sukhanov, S., Kolls, J., Kim, W.-K., Delafontaine, P., Rappaport, J., Qin, X., Rout, N.
Abstract
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: preinfection, 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 NFkB signaling, coupled with suppression of T cell 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, NFkB, and inflammasome (NLRP3 or NLRP12, caspase1) signaling, along with sustained macrophage activation, platelet/coagulation signaling, and senescence-associated secretory phenotype. Protein analyses confirmed persistent CASPASE1 and NFkB activation in spleen tissue. Pathologic evaluation of a carotid artery from an SIV infected, long term ART treated macaque revealed macrophages in plaques with p21 expressing; senescent cells with intraluminal thrombus formation, recapitulating key features of HIV associated atherogenesis. Together, these findings demonstrate that 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, NFkB, and senescence pathways may mitigate nonAIDS comorbidities in PLWH.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 07 Nov 2025.
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