Immune profile and mitochondrial alterations driven by age and HIV infection: Associations with T-cell senescence in people with HIV receiving suppressive antiretroviral therapy

Junyan Jin; Xin Zhang; Qianqian Xu; Wei Xia; Hongxia Yan; Hao Wu; Christiane Moog; Tong Zhang; Bin Su

doi:10.1016/j.virs.2026.05.001

June 2026

Citation: Junyan Jin, Xin Zhang, Qianqian Xu, Wei Xia, Hongxia Yan, Hao Wu, Christiane Moog, Tong Zhang, Bin Su. Immune profile and mitochondrial alterations driven by age and HIV infection: Associations with T-cell senescence in people with HIV receiving suppressive antiretroviral therapy .VIROLOGICA SINICA, 2026, 41(3) : 561-573. http://dx.doi.org/10.1016/j.virs.2026.05.001

Immune profile and mitochondrial alterations driven by age and HIV infection: Associations with T-cell senescence in people with HIV receiving suppressive antiretroviral therapy

Junyan Jin ^a,b ,
Xin Zhang ^a,b ,
Qianqian Xu ^a,b ,
Wei Xia ^a,b ,
Hongxia Yan ^a,b ,
Hao Wu ^a,b ,
Christiane Moog ^b,c ,
Tong Zhang ^{a,b
,,} ,
Bin Su ^{a,b,d,e
,,}

a. Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China;
b. Sino-French Joint Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China;
c. Laboratoire d'ImmunoRhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1109, Institut Thématique Interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, 67000, France;
d. Central Laboratory, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China;
e. The Scientific and Technological Achievement Transformation Center, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China

Corresponding author: Tong Zhang, zt_doc@ccmu.edu.cn
Bin Su, binsu@ccmu.edu.cn
Received Date: 11 January 2026
Accepted Date: 09 May 2026
Available online: 14 May 2026

Abstract

Antiretroviral therapy (ART) has significantly extended the life expectancy of people with HIV (PWH), rendering population ageing and immunosenescence prominent clinical priorities. T-cell senescence is linked to mitochondrial dysfunction and drives age-related immune remodelling, yet how HIV infection and ageing jointly shape CD4⁺ and CD8⁺ T-cell immunophenotypes and mitochondrial remodelling remains unclear. This cross-sectional study included 61 PWH on suppressive ART for ≥ 12 months and 61 age- and sex-matched HIV-negative men who have sex with men, stratified into younger (≤ 35 years) and older (≥ 50 years) groups. Multiparameter flow cytometry was used to profile CD4⁺ and CD8⁺ T-cell differentiation, stemness, activation/exhaustion, and metabolic phenotypes, together with mitochondrial mass and membrane potential. We found that ageing and HIV infection were associated with T-cell remodelling, characterized by expanded late-differentiated phenotypes and reduced stem-like, homeostatic and costimulatory CD4⁺ and CD8⁺ T-cell subsets, as indicated by upregulated CD57 and CX3CR1 and downregulated CD45RA⁺CD31⁺, FOXO1, and CD28. Notably, younger PWH had an ageing-like CD4⁺ T-cell profile, with higher CD57, CX3CR1 and TIGIT expression than younger HIV-negative individuals. In contrast, HIV-related CD8⁺ T-cell perturbations (KLRG1, CXCR3, NKG2C and CD95) were more pronounced in older PWH. PWH exhibited increased mitochondrial mass and membrane potential in both total and senescent-like CD4⁺ and CD8⁺ T cells, particularly in CD8⁺ T cells from older PWH. In CD4⁺ T cells, KLRG1 and CX3CR1 expression correlated positively with age, and inversely with CD4⁺ T-cell counts and CD4/CD8 ratio. By contrast, FOXO1 expression in CD8⁺ T cells was inversely associated with age, late-differentiation markers, and ART duration in PWH. Overall, age is a major driver of T-cell immunosenescence, and HIV infection modulates and exacerbates these alterations. Mitochondrial stress, FOXO1 downregulation and immune network remodelling support a multifaceted model of HIV-associated immune ageing that may contribute to heterogeneous immune reconstitution in PWH, highlighting potential targets to mitigate immune ageing.
- HIV infection
- , Ageing
- , Immunosenescence
- , T cells
- , Mitochondrial dysfunction

References
1. Akbar, A.N., Henson, S.M.,Lanna, A., 2016. Senescence of T Lymphocytes: Implications for Enhancing Human Immunity. Trends Immunol, 37, 866-876.
2. Akiso, M., Ameka, M., Naidoo, K., Langat, R., Kombo, J., Sikuku, D., Ndung'u, T., Altfeld, M., Anzala, O.,Mureithi, M., 2023. Metabolic and mitochondrial dysregulation in CD4+ T cells from HIV-positive women on combination anti-retroviral therapy. PLoS One, 18, e0286436.
3. Akiyama, M., Wakasugi, S., Yoshimoto, K., Saito, K., Ishigaki, S., Inukai, R., Matsuno, Y., Alshehri, W., Kondo, Y.,Kaneko, Y., 2025. CX3CR1(+) age-associated CD4(+) T cells contribute to synovial inflammation in late-onset rheumatoid arthritis. Inflammation & Regeneration, 45, 4.
4. Brenchley, J.M., Karandikar, N.J., Betts, M.R., Ambrozak, D.R., Hill, B.J., Crotty, L.E., Casazza, J.P., Kuruppu, J., Migueles, S.A., Connors, M., Roederer, M., Douek, D.C.,Koup, R.A., 2003. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood, 101, 2711-2720.
5. Callender, L.A., Carroll, E.C., Bober, E.A., Akbar, A.N., Solito, E.,Henson, S.M., 2020. Mitochondrial mass governs the extent of human T cell senescence. Aging Cell, 19, e13067.
6. Chan, Y.T., Loh, K.M., Phong, Z.Y., Tang, T.F., Ng, C.H., Saeidi, A., Cheong, H.C., Cheok, Y.Y., Ng, R.X., Azwa, R., Cheng, K.K., Looi, C.Y., Kamarulzaman, A., Rajasuriar, R.,Wong, W.F., 2025. Exhausted CD8(+) T Cell in HIV Infection Exhibits an Impaired Bioenergetic Metabolism Driven by Mitochondrial Dysfunction. Immunology, 10.1111/imm.70054.
7. Chauvin, M.,Sauce, D., 2022. Mechanisms of immune aging in HIV. Clin Sci (Lond), 136, 61-80.
8. Choi, M., Choi, S., Cho, M.,Kim, C., 2025. Metabolic Signaling as a Driver of T Cell Aging. Immune Netw, 25, e14.
9. De Francesco, D., Wit, F.W., Burkle, A., Oehlke, S., Kootstra, N.A., Winston, A., Franceschi, C., Garagnani, P., Pirazzini, C., Libert, C., Grune, T., Weber, D., Jansen, E., Sabin, C.A.,Reiss, P., 2019. Do people living with HIV experience greater age advancement than their HIV-negative counterparts? Aids, 33, 259-268.
10. Delpoux, A., Marcel, N., Hess Michelini, R., Katayama, C.D., Allison, K.A., Glass, C.K., Quinones-Parra, S.M., Murre, C., Loh, L., Kedzierska, K., Lappas, M., Hedrick, S.M.,Doedens, A.L., 2021. FOXO1 constrains activation and regulates senescence in CD8 T cells. Cell Rep, 34, 108674.
11. Dolfi, D.V., Mansfield, K.D., Polley, A.M., Doyle, S.A., Freeman, G.J., Pircher, H., Schmader, K.E.,Wherry, E.J., 2013. Increased T-bet is associated with senescence of influenza virus-specific CD8 T cells in aged humans. J Leukoc Biol, 93, 825-836.
12. Durstenfeld, M.S., Wilson, M.P., Jankowski, C.M., Ditzenberger, G.L., Longenecker, C.T.,Erlandson, K.M., 2024. Chronotropic Incompetence Among People With HIV Improves With Exercise Training in the Exercise for Healthy Aging Study. J Infect Dis, 230, 919-927.
13. Eke, A.C.,Eke, U.A., 2025. Beyond Viral Suppression: Navigating Structural Barriers, Aging and Frailty, Drug Resistance, Therapeutic Innovations, and Reproductive Health Challenges in the Global HIV/AIDS Epidemic. J AIDS HIV Treat, 7, 108-122.
14. Elias Junior, E., Gubert, V.T., Bonin-Jacob, C.M., Puga, M.a.M., Gouveia, C.G., Sichinel, A.H.,Tozetti, I.A., 2024. CD57 T cells associated with immunosenescence in adults living with HIV or AIDS. Immunology, 171, 146-153.
15. Escrig-Larena, J.I., Delgado-Pulido, S.,Mittelbrunn, M., 2023. Mitochondria during T cell aging. Semin Immunol, 69, 101808.
16. Fang, F., Cao, W., Zhu, W., Lam, N., Li, L., Gaddam, S., Wang, Y., Kim, C., Lambert, S., Zhang, H., Hu, B., Farber, D.L., Weyand, C.M.,Goronzy, J.J., 2021. The cell-surface 5'-nucleotidase CD73 defines a functional T memory cell subset that declines with age. Cell Rep, 37, 109981.
17. Hoffmann, J.P., Liu, J.A., Seddu, K.,Klein, S.L., 2023. Sex hormone signaling and regulation of immune function. Immunity, 56, 2472-2491.
18. Hove-Skovsgaard, M., Zhao, Y., Tingstedt, J.L., Hartling, H.J., Thudium, R.F., Benfield, T., Afzal, S., Nordestgaard, B., Ullum, H., Gerstoft, J., Mocroft, A.,Nielsen, S.D., 2020. Impact of Age and HIV Status on Immune Activation, Senescence and Apoptosis. Front Immunol, 11, 583569.
19. Humblin, E., Korpas, I., Lu, J., Filipescu, D., Van Der Heide, V., Goldstein, S., Vaidya, A., Soares-Schanoski, A., Casati, B., Selvan, M.E., Gumus, Z.H., Wieland, A., Corrado, M., Cohen-Gould, L., Bernstein, E., Homann, D., Chipuk, J.,Kamphorst, A.O., 2023. Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1(+) PD-1(+) CD8 T cells. Sci Immunol, 8, eadg0878.
20. Jin, J., Li, X., Hu, B., Kim, C., Cao, W., Zhang, H., Weyand, C.M.,Goronzy, J.J., 2020. FOXO1 deficiency impairs proteostasis in aged T cells. Sci Adv, 6, eaba1808.
21. Jin, J., Xu, Q., Zhang, X., Zhu, A., Xia, W., Moog, C., Chan, A.S.W., Zhang, T.,Su, B., 2025. HIV infection and immunosenescence: challenges and intervention strategies. BMC Med, 24, 8.
22. Kaplan-Lewis, E., Aberg, J.A.,Lee, M., 2017. Aging with HIV in the ART era. Semin Diagn Pathol, 34, 384-397.
23. Lagathu, C., Cossarizza, A., Bereziat, V., Nasi, M., Capeau, J.,Pinti, M., 2017. Basic science and pathogenesis of ageing with HIV: potential mechanisms and biomarkers. Aids, 31 Suppl 2, S105-s119.
24. Li, N., Zheng, H.Y., Li, W., He, X.Y., Zhang, M., Li, X., Tian, R.R., Dong, X.Q., Shen, Z.Q.,Zheng, Y.T., 2025. Limited restoration of T cell subset distribution and immune function in older people living with HIV-1 receiving HAART. Immun Ageing, 22, 3.
25. Liu, Z., Liang, Q., Ren, Y., Guo, C., Ge, X., Wang, L., Cheng, Q., Luo, P., Zhang, Y.,Han, X., 2023. Immunosenescence: molecular mechanisms and diseases. Signal Transduct Target Ther, 8, 200.
26. Luo, L., Lechuga-Vieco, A.V., Sattentau, C., Borsa, M.,Simon, A.K., 2025. Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms. EMBO Rep, 26, 4402-4418.
27. Ma, L., Wang, X.,Xu, H., 2025. Mitochondrial DNA damage in HIV infection: a mechanistic driver of immunometabolic dysfunction and chronic inflammation. Front Immunol, 16, 1722463.
28. Mittelbrunn, M.,Kroemer, G., 2021. Hallmarks of T cell aging. Nat Immunol, 22, 687-698.
29. Mo, Y., Yue, M., Yim, L.Y., Zhou, R., Yu, C., Peng, Q., Zhou, Y., Luk, T.Y., Lui, G.C., Huang, H., Lim, C.Y.H., Wang, H., Liu, L., Sun, H., Wang, J., Song, Y.,Chen, Z., 2023. Nicotinamide mononucleotide impacts HIV-1 infection by modulating immune activation in T lymphocytes and humanized mice. EBioMedicine, 98, 104877.
30. Quinn, K.M., Palchaudhuri, R., Palmer, C.S.,La Gruta, N.L., 2019. The clock is ticking: the impact of ageing on T cell metabolism. Clin Transl Immunology, 8, e01091.
31. Rinaldi, S., Pallikkuth, S., De Armas, L., Richardson, B., Pan, L., Pahwa, R., Williams, S., Cameron, M.,Pahwa, S., 2022. Distinct Molecular Signatures of Aging in Healthy and HIV-Infected Individuals. J Acquir Immune Defic Syndr, 89, S47-s55.
32. Rodes, B., Cadinanos, J., Esteban-Cantos, A., Rodriguez-Centeno, J.,Arribas, J.R., 2022. Ageing with HIV: Challenges and biomarkers. EBioMedicine, 77, 103896.
33. Rodrigues, L.P., Teixeira, V.R., Alencar-Silva, T., Simonassi-Paiva, B., Pereira, R.W., Pogue, R.,Carvalho, J.L., 2021. Hallmarks of aging and immunosenescence: Connecting the dots. Cytokine & Growth Factor Reviews, 59, 9-21.
34. Rodriguez, I.J., Lalinde Ruiz, N., Llano Leon, M., Martinez Enriquez, L., Montilla Velasquez, M.D.P., Ortiz Aguirre, J.P., Rodriguez Bohorquez, O.M., Velandia Vargas, E.A., Hernandez, E.D.,Parra Lopez, C.A., 2020. Immunosenescence Study of T Cells: A Systematic Review. Front Immunol, 11, 604591.
35. Sainz, T., Serrano-Villar, S., Diaz, L., Gonzalez Tome, M.I., Gurbindo, M.D., De Jose, M.I., Mellado, M.J., Ramos, J.T., Zamora, J., Moreno, S.,Munoz-Fernandez, M.A., 2013. The CD4/CD8 ratio as a marker T-cell activation, senescence and activation/exhaustion in treated HIV-infected children and young adults. Aids, 27, 1513-1516.
36. Samuels, R., Bayerri, C.R., Sayer, J.A., Price, D.A.,Payne, B.a.I., 2017. Tenofovir disoproxil fumarate-associated renal tubular dysfunction: noninvasive assessment of mitochondrial injury. Aids, 31, 1297-1301.
37. Sanchez-Conde, M., Diaz-Alvarez, J., Dronda, F.,Branas, F., 2019. Why are people with HIV considered "older adults" in their fifties? Eur Geriatr Med, 10, 183-188.
38. Siedner, M.J., 2019. Aging, Health, and Quality of Life for Older People Living With HIV in Sub-Saharan Africa: A Review and Proposed Conceptual Framework. Journal of Aging & Health, 31, 109-138.
39. Spinelli, J.B.,Haigis, M.C., 2018. The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol, 20, 745-754.
40. Sturmlechner, I., Jain, A., Mu, Y., Weyand, C.M.,Goronzy, J.J., 2023. T cell fate decisions during memory cell generation with aging. Semin Immunol, 69, 101800.
41. Teeraananchai, S., Kerr, S.J., Amin, J., Ruxrungtham, K.,Law, M.G., 2017. Life expectancy of HIV-positive people after starting combination antiretroviral therapy: a meta-analysis. HIV Med, 18, 256-266.
42. Vassallo, M., Durant, J., Addou, S., Ticchioni, M., Fabre, R., Chirio, D., Naqvi, A., Cua, E., Ameil, L., Godemert, M., Pradier, C.,Carles, M., 2025. Immunosenescence markers in T- and NK-cells according to the CD4/CD8 ratio in successfully treated people living with HIV. Front Med (Lausanne), 12, 1562537.
43. Weinberg, S.E.,Chandel, N.S., 2025. Mitochondria reactive oxygen species signaling-dependent immune responses in macrophages and T cells. Immunity, 58, 1904-1921.
44. Zhang, Y., Chen, S., Tang, X., Peng, Y., Jiang, T., Zhang, X., Li, J., Liu, Y.,Yang, Z., 2024. The role of KLRG1: a novel biomarker and new therapeutic target. Cell Commun Signal, 22, 337.
45. Zwijnenburg, A.J., Pokharel, J., Varnaite, R., Zheng, W., Hoffer, E., Shryki, I., Comet, N.R., Ehrstrom, M., Gredmark-Russ, S., Eidsmo, L.,Gerlach, C., 2023. Graded expression of the chemokine receptor CX3CR1 marks differentiation states of human and murine T cells and enables cross-species interpretation. Immunity, 56, 1955-1974.e1910.
Proportional views

Figures(1)

PDF

Article Metrics

Article views(28) PDF downloads(0) Cited by()

Immune profile and mitochondrial alterations driven by age and HIV infection: Associations with T-cell senescence in people with HIV receiving suppressive antiretroviral therapy

Abstract

References

Proportional views

Article Metrics

Related

Proportional views

Immune profile and mitochondrial alterations driven by age and HIV infection: Associations with T-cell senescence in people with HIV receiving suppressive antiretroviral therapy

Corresponding author: Tong Zhang, zt_doc@ccmu.edu.cn

Corresponding author: Bin Su, binsu@ccmu.edu.cn

HTML

目录