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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02531

ATM deficiency accelerates DNA damage, telomere erosion, and premature T cell aging in HIV-infected individuals on antiretroviral therapy

 Zhi Q. Yao1*,  Juan Zhao1,  Lam N. Nguyen1,  Lam N. Nguyen1, Xindi Dang1,  Dechao Cao1, Sushant Khanal1,  Madison Schank1,  Bal Krishna Chand Thakuri1, Zheng D. Morrison1, Xiaoyuan Wu1,  Yue Zou1,  Mohamed Elgazzar1, Shunbin Ning1, Ling Wang1 and Jonathan Moorman1
  • 1East Tennessee State University, United States

HIV infection leads to a phenomenon of inflammaging, in which chronic inflammation induces an immune aged phenotype, even in individuals on combined antiretroviral therapy (cART) with undetectable viremia. In this study, we investigated T cell homeostasis and telomeric DNA damage and repair machineries in cART-controlled HIV patients at risk for inflammaging. We found a significant depletion of CD4 T cells, which was inversely correlated with the cell apoptosis in virus-suppressed HIV subjects compared to age-matched healthy subjects (HS). In addition, HIV CD4 T cells were prone to DNA damage that extended to chromosome ends - telomeres, leading to accelerated telomere erosion - a hallmark of cell senescence. Mechanistically, the DNA double-strand break (DSB) sensors MRE11, RAD50, and NBS1 (MRN) remained intact, but both expression and activity of the DNA damage checkpoint kinase ataxia-telangiectasia mutated (ATM) and its downstream checkpoint kinase 2 (CHK2) were significantly suppressed in HIV CD4 T cells. Consistently, ATM/CHK2 activation, DNA repair, and cellular functions were also impaired in healthy CD4 T cells following ATM knockdown or exposure to the ATM inhibitor KU60019 in vitro, recapitulating the biological effects observed in HIV-derived CD4 T cells in vivo. Importantly, ectopic expression of ATM was essential and sufficient to reduce the DNA damage, apoptosis, and cellular dysfunction in HIV-derived CD4 T cells. These results demonstrate that failure of DSB repair due to ATM deficiency leads to increased DNA damage and renders CD4 T cells prone to senescence and apoptotic death, contributing to CD4 T cell depletion or dysfunction in cART-controlled, latent HIV infection.

Keywords: ATM, Apoptosis, DNA damage repair, Immune aging, HIV, T cell homeostasis

Received: 20 Apr 2019; Accepted: 11 Oct 2019.

Copyright: © 2019 Yao, Zhao, Nguyen, Nguyen, Dang, Cao, Khanal, Schank, Chand Thakuri, Morrison, Wu, Zou, Elgazzar, Ning, Wang and Moorman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Zhi Q. Yao, East Tennessee State University, Johnson City, United States, yao@etsu.edu