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Vol 56(2022) N 5 p. 713-722; DOI 10.1134/S0026893322050041 Full Text

S.A. Brezgin1,2, A.P. Kostyusheva1*, N.I. Ponomareva1,2, V.I. Gegechkori3, N.P. Kirdyashkina4, S.R. Ayvasyan5, L.N. Dmitrieva5, L.N. Kokoreva5, V.P. Chulanov1,2,5,6, D.S. Kostyushev1,2

HBx Protein Potentiates Hepatitis B Virus Reactivation

1Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov First Moscow State Medical University, Ministry of Healthcare of the Russian Federation (Sechenov University), Moscow, 119048 Russia
2Sirius University of Science and Technology, Sochi, 354340 Russia
3Department of Pharmaceutical and Toxicological Chemistry, Sechenov First Moscow State Medical University, Ministry of Healthcare of the Russian Federation (Sechenov University), Moscow, 119991 Russia
4Izmerov Research Institute of Occupational Health, Moscow, 105275 Russia
5Department of Infectious Diseases, Sechenov First Moscow State Medical University, Ministry of Healthcare of the Russian Federation (Sechenov University), Moscow, 119048 Russia
6National Medical Research Center for Tuberculosis and Infectious Diseases, Moscow, 127994 Russia

*dkostushev@gmail.com
Received - 2022-03-31; Revised - 2022-03-31; Accepted - 2022-04-12

Hepatitis B virus (HBV) can cause chronic hepatitis B, one of the most prevalent infectious diseases in the world. Global estimates suggest that over 2 billion people are affected by HBV, with over 250 million people developing chronic infection. Upon treatment of comorbidities, patients with chronic infection may develop an abrupt increase of viral replication-HBV reactivation-leading to liver decompensation and, in some cases, death. HBV reactivation occurs mostly due to suppression of antiviral immune response and activation of intracellular pro-viral signaling. Defining the mechanisms of HBV reactivation is necessary for the rational use of drugs and reduction of mortality rates in patients with chronic infection. In this study, for the first time we analyzed the effects of HBx protein on HBV reactivation, described reactivation of HBV from the transcriptionally inactivated state at the methylated recombinant HBV genome model, and investigated HBV reactivation upon treatment with genotoxic agents (doxorubicin and hydrogen peroxide) and targeted drug therapies (sunitinib and bortezomib). We report that both wild-type HBx protein and, to a greater extent, the mutant form of HBx protein lacking the nuclear exportation signal, potentiate viral replication and promote HBV reactivation. For the first time, we demonstrate that HBV can reactivate from the transcriptionally inactive state. Doxorubicin and hydrogen peroxide induce HBV reactivation at models of both transcriptionally active and transcriptionally silenced viral genome. Sunitinib weakly reactivates HBV, while bortezomib does not affect HBV replication in vitro.

ATM, ATR, Chk1/2, cccDNA, HBV DNA, viral load, DNA damage, anticancer therapies, comorbidities



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