ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage.

Anastasiya Kostyusheva,Elena Volchkova,Vladimir Chulanov,Ilya Gordeychuk,Ekaterina Bayurova,Sergey Brezgin,Felix Urusov,Irina Goptar,Maria Isaguliants,Dmitry Kostyushev,Anastasiya Nikiforova

doi:10.3390/v11110997

Abstract

Chronic hepatitis B virus infection (CHB) caused by the hepatitis B virus (HBV) is one of the most common viral infections in the world. Reactivation of HBV infection is a life-threatening condition observed in patients with CHB receiving chemotherapy or other medications. Although HBV reactivation is commonly attributed to immune suppression, other factors have long been suspected to play a role, including intracellular signaling activated in response to DNA damage. We investigated the effects of DNA-damaging factors (doxorubicin and hydrogen peroxide) on HBV reactivation/replication and the consequent DNA-damage response. Dose-dependent activation of HBV replication was observed in response to doxorubicin and hydrogen peroxide which was associated with a marked elevation in the mRNA levels of ataxia-telangiectasia mutated (ATM) and ATM- and RAD3-related (ATR) kinases. Downregulation of ATM or ATR expression by shRNAs substantially reduced the levels of HBV RNAs and DNA. In contrast, transcriptional activation of ATM or ATR using CRISPRa significantly increased HBV replication. We conclude that ATM and ATR are essential for HBV replication. Furthermore, DNA damage leading to the activation of ATM and ATR transcription, results in the reactivation of HBV replication.

Highlights

Hepatitis B virus (HBV) causes acute or chronic hepatitis B virus infection (CHB) [1]
Transcriptional activation of ataxia-telangiectasia mutated (ATM) or ATMand RAD3-related (ATR) using the CRISPRa technique [29] potentiates HBV replication, mimicking the effects of DNA-damaging agents. These findings indicate that ATM and ATR play an important role in the reactivation of HBV replication switching it upon DNA damage
Earlier studies demonstrated that replication of HBV in human cells results in DNA

Summary

Introduction

Hepatitis B virus (HBV) causes acute or chronic hepatitis B virus infection (CHB) [1]. Comorbidities in patients with CHB often require additional interventions, such as cancer chemotherapy, immunosuppressive therapies after liver transplantation, treatment of viral hepatitis C in HBV-HCV-co-infected individuals which may trigger an abrupt reactivation of HBV infection [4,5]. In patients undergoing chemotherapy and therapy with immunosuppressive drugs, treatment may result in lethal HBV reactivation [6,7,8]. This turns HBV reactivation into a serious clinical problem posing a major threat to global public health

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