Telomere and ATM Dynamics in CD4 T-Cell Depletion in Active and Virus-Suppressed HIV Infections
Sushant Khanal, Qiyuan Tang, Dechao Cao, Juan Zhao, Lam Nhat Nguyen, Oluwayomi Samson Oyedeji, Xindi Dang, Lam Ngoc Thao Nguyen, Madison Schank, Bal Krishna Chand Thakuri, Chinyere Ogbu, Zheng D. Morrison, Xiao Y. Wu, Zheng Zhang, Qing‐Yu He, Mohamed El Gazzar, Zhengke Li, Shunbin Ning, Ling Wang, Jonathan P. Moorman, Zhi Q. Yao
Abstract
The hallmark of HIV infection is a gradual depletion of CD4 T cells, with a progressive decline of host immunity. How CD4 T cells are depleted in individuals with active and virus-suppressed HIV infection remains unclear. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the chromosome end (telomere) DNA damage response (DDR) and cellular apoptosis in a T-cell line (highly permissive SupT1 cells), as well as in primary CD4 T cells with active or drug-suppressed HIV infection. We demonstrated that HIV-induced telomeric DDR plays a critical role in inducing telomere loss, premature cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This study sheds new light on the molecular mechanisms of telomeric DDR and its role in CD4 T-cell homeostasis during HIV infection.