Xin Zhong ^1,2,3,4 ChengBo Song ^1,2,3,5,6,7 DingNing Liu ^1,3,4 Mei Liu ^1,3,4 YaJing Fu ^1,2,3,4 HaiBo Ding ^1,2,3,4 YongJun Jiang ^1,2,3,4 Hong Shang ^1,2,3,4* ZiNing Zhang ^1,2,3,4

• ¹ NHC Key Laboratory of AIDS Immunology (China Medical University), National Clinical Research Center for Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
• ² Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, China., Shenyang, Liaoning Province, China
• ³ Units of Medical Laboratory, Chinese Academy of Medical Sciences, Shenyang, China
• ⁴ Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
• ⁵ School of Public Health, China Medical University, Shenyang, Liaoning Province, China
• ⁶ China Medical University, Shenyang, Liaoning Province, China
• ⁷ The Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, China Medical University, Shenyang, Liaoning Province, China

Antiretroviral therapy (ART) is effective in suppressing human immunodeficiency virus (HIV) replication, but it cannot completely restore HIV-induced chronic immune activation and subsequent "inflamm-aging". CD38 is well known as a classic activation marker, whose expression is a very salient aspect of chronic activation. However, as a nicotinamide adenine dinucleotide (NAD) hydrolase, the biological effects of CD38 overexpression on T cell function in HIV infection have not been fully elucidated. Here we demonstrate that high CD38 expression on T cells correlated with T cell immune senescence by affecting mitochondrial homeostasis in HIV infection.Transcriptomics analysis revealed that malic enzyme 1 (ME1), a tricarboxylic acid (TCA) cycleassociated enzyme, is significantly downregulated in CD38 + T cells. Inhibition of ME1 could impair mitochondrial fitness, leading to cellular senescence in T cells. Further study showed that CD38 expression could induce p53 acetylation through the reduction of NAD+-dependent SIRT1 deacetylase activity, which contributes to the reduction of ME1 levels. Importantly, we found that both CD38 inhibitor, 78c, and the SIRT1-related senolytic drug, quercetin, could interfere with CD38-mediated T cell senescence in HIV-infected individuals. These findings highlighted a novel strategy to improve CD38-mediated T cell dysfunction, mitochondrial damage, and immune senescence, providing new targets for clinical intervention of immune senescence in HIV infection.