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posted on 04.05.2021, 04:45 by Juan Zhao, Madison Schank, Ling Wang, Zhengke Li, Lam Nhat Nguyen, Xindi Dang, Dechao Cao, Sushant Khanal, Lam Ngoc Thao Nguyen, Bal Krishna Chand Thakuri, Stella C. Ogbu, Zeyuan Lu, Xiao Y. Wu, Zheng D. Morrison, Mohamed El Gazzar, Ying Liu, Jinyu Zhang, Shunbin Ning, Jonathan P. Moorman, Zhi Q. Yao

The hallmark of HIV/AIDS is a gradual depletion of CD4 T cells. Despite effective control by antiretroviral therapy (ART), a significant subgroup of people living with HIV (PLHIV) fails to achieve complete immune reconstitution, deemed as immune non-responders (INRs). The mechanisms underlying incomplete CD4 T cell recovery in PLHIV remain unclear. In this study, CD4 T cells from PLHIV were phenotyped and functionally characterized, focusing on their mitochondrial functions. The results show that while total CD4 T cells are diminished, cycling cells are expanded in PLHIV, especially in INRs. HIV-INR CD4 T cells are more activated, displaying exhausted and senescent phenotypes with compromised mitochondrial functions. Transcriptional profiling and flow cytometry analysis showed remarkable repression of mitochondrial transcription factor A (mtTFA) in CD4 T cells from PLHIV, leading to abnormal mitochondrial and T cell homeostasis. These results demonstrate a sequential cellular paradigm of T cell over-activation, proliferation, exhaustion, senescence, apoptosis, and depletion, which correlates with compromised mitochondrial functions. Therefore, reconstituting the mtTFA pathway may provide an adjunctive immunological approach to revitalizing CD4 T cells in ART-treated PLHIV, especially in INRs.

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