Pathogenic SIV infection is associated with acceleration of epigenetic age in rhesus macaques
Anna J. Jasinska, … , Cristian Apetrei, Ivona Pandrea
Anna J. Jasinska, … , Cristian Apetrei, Ivona Pandrea
Published July 15, 2025
Citation Information: J Clin Invest. 2025;135(14):e189574. https://doi.org/10.1172/JCI189574.
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Research Article AIDS/HIV Infectious disease

Pathogenic SIV infection is associated with acceleration of epigenetic age in rhesus macaques

Abstract

HIV infection accelerates biological aging, but the contribution of the host’s age to this process is unknown. We investigated the influence of SIV infection in macaques (SIVmac) on the risk of comorbidities and aging in young and old rhesus macaques (RMs) by assessing pathogenesis markers, DNA methylation–based epigenetic age (EA), and EA acceleration (EAA) in blood and tissues. Initially, upon SIV infection, the young RMs showed greater resilience to CD4+ T cell depletion, better control of T cell activation, hypercoagulation, and excessive inflammation, yet this resilience was progressively lost in the advanced stages of infection. During the late stages of infection, the young RMs, but not the aged ones, showed an increase in EA in PBMCs; also, EAA in the cerebellum and heart of young RMs was higher compared with old RMs. SIV infection was more pathogenic in aged animals in early stages, leading to a more rapid disease progression; however, accelerated aging mostly affected young animals, so that the levels of multiple key pathogenesis markers in the young RMs converged toward those specific to aged ones in the late stages of infection. We conclude that SIV infection–driven age acceleration is tissue specific, and that host age influences the susceptibility of different tissues to enhanced aging.

Authors

Anna J. Jasinska, Ranjit Sivanandham, Sindhuja Sivanandham, Cuiling Xu, Juozas Gordevicius, Milda Milčiūtė, Robert T. Brooke, Paola Sette, Tianyu He, Egidio Brocca-Cofano, Benjamin B. Policicchio, Krishna Nayak, Saharsh Talwar, Haritha Annapureddy, Dongzhu Ma, Ruy M. Ribeiro, Cristian Apetrei, Ivona Pandrea

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Figure 5

Longitudinal DNAme analysis of PBMCs.

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Longitudinal DNAme analysis of PBMCs. (A) Epigenome-wide association stu...
(A) Epigenome-wide association study of dpi in PBMCs based on the entire methylation array. The volcano plots display the −log10 (P values) and the directionality of association between CpG sites and infection stages (A, EC, and LC) compared with B: A versus B (left panel), EC versus B (center panel), and LC versus B (right panel). Each dot represents a specific DNAme site. Shown are significantly associated CpG sites (q < 0.05) with hypomethylation (blue), hypermethylation (red), and nonsignificant (gray). The horizontal axis represents the mean methylation change (i.e., the difference between group means), and the vertical axis represents −log10 (P values). (B) Changes in EA during each infection stage (A, EC, and LC) relative to B. Biological age analysis was performed based on subsets of clock CpGs. EA at the 3 infection time points was compared with B using mixed-effects linear regression modeling of longitudinal EA changes in PBMCs based on 10 epigenetic clocks. The results are shown separately for young (right) and old (left) RMs. Epigenetic age changes in young (blue) and old (red) RMs are shown. Saturated colors indicate statistically significant changes (P < 0.05); pale colors indicate nonsignificant changes (P > 0.05). A statistically significant increase in EA was observed only in young RMs. B–H, Benjamini–Hochberg correction; DMP, differentially methylated positions; dpi, days after infection; RMs, rhesus macaques; B, baseline; A, acute; EC, early chronic; LC, late chronic; EA, epigenetic age.