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      Enterovirus 71 antagonizes the inhibition of the host intrinsic antiviral factor A3G


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          Although the host restriction factor APOBEC3G (A3G) has broad spectrum antiviral activity, whether A3G inhibits enterovirus 71 (EV71) has been unclear until now. In this study, we demonstrated for the first time that A3G could inhibit EV71 virus replication. Silencing A3G in H9 cells enhanced EV71 replication, and EV71 replication was lower in H9 cells expressing A3G than in Jurkat cells without A3G expression, indicating that the EV71 inhibition was A3G-specific. Further investigation revealed that A3G inhibited the 5′UTR activity of EV71 by competitively binding to the 5′UTR through its nucleic acid binding activity. This binding impaired the interaction between the 5′UTR and the host protein poly(C)-binding protein 1 (PCBP1), which is required for the synthesis of EV71 viral proteins and RNA. On the other hand, we found that EV71 overcame A3G suppression through its non-structural protein 2C, which induced A3G degradation through the autophagy–lysosome pathway. Our research provides new insights into the interplay mechanisms of A3G and single-stranded positive RNA viruses.

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          Most cited references49

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          An apparently new enterovirus isolated from patients with disease of the central nervous system.

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            An overview of the evolution of enterovirus 71 and its clinical and public health significance.

            Since its discovery in 1969, enterovirus 71 (EV71) has been recognised as a frequent cause of epidemics of hand-foot-and-mouth disease (HFMD) associated with severe neurological sequelae in a small proportion of cases. There has been a significant increase in EV71 epidemic activity throughout the Asia-Pacific region since 1997. Recent HFMD epidemics in this region have been associated with a severe form of brainstem encephalitis associated with pulmonary oedema and high case-fatality rates. The emergence of large-scale epidemic activity in the Asia-Pacific region has been associated with the circulation of three genetic lineages that appear to be undergoing rapid evolutionary change. Two of these lineages (B3 and B4) have not been described previously and appear to have arisen from an endemic focus in equatorial Asia, which has served as a source of virus for HFMD epidemics in Malaysia, Singapore and Australia. The third lineage (C2) has previously been identified [Brown, B.A. et al. (1999) J. Virol. 73, 9969-9975] and was primarily responsible for the large HFMD epidemic in Taiwan during 1998. As EV71 appears not to be susceptible to newly developed antiviral agents and a vaccine is not currently available, control of EV71 epidemics through high-level surveillance and public health intervention needs to be maintained and extended throughout the Asia-Pacific region. Future research should focus on (1) understanding the molecular genetics of EV71 virulence, (2) identification of the receptor(s) for EV71, (3) development of antiviral agents to ameliorate the severity of neurological disease and (4) vaccine development to control epidemics. Following the successful experience of the poliomyelitis control programme, it may be possible to control EV71 epidemics if an effective live-attenuated vaccine is developed.
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              HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation.

              The viral infectivity factor (Vif) encoded by HIV-1 neutralizes a potent antiviral pathway that occurs in human T lymphocytes and several leukemic T-cell lines termed nonpermissive, but not in other cells termed permissive. In the absence of Vif, this antiviral pathway efficiently inactivates HIV-1. It was recently reported that APOBEC3G (also known as CEM-15), a cytidine deaminase nucleic acid-editing enzyme, confers this antiviral phenotype on permissive cells. Here we describe evidence that Vif binds APOBEC3G and induces its rapid degradation, thus eliminating it from cells and preventing its incorporation into HIV-1 virions. Studies of Vif mutants imply that it contains two domains, one that binds APOBEC3G and another with a conserved SLQ(Y/F)LA motif that mediates APOBEC3G degradation by a proteasome-dependent pathway. These results provide promising approaches for drug discovery.

                Author and article information

                Nucleic Acids Res
                Nucleic Acids Res
                Nucleic Acids Research
                Oxford University Press
                30 November 2018
                21 September 2018
                21 September 2018
                : 46
                : 21
                : 11514-11527
                [1 ]The First Hospital of Jilin University, Institute of Virology and AIDS Research, Changchun 130021, PR China
                [2 ]Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education), Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, PR China
                Author notes
                To whom correspondence should be addressed. Tel: +86 431 88782148; Fax: +86 431 85654528; Email: zhangwenyan@ 123456jlu.edu.cn
                © The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 11 September 2018
                : 23 August 2018
                : 16 June 2018
                Page count
                Pages: 14
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81672004
                Award ID: 31270202
                Award ID: 81701987
                Funded by: Jilin University Science and Technology 10.13039/100009977
                Award ID: 2017TD-05
                Funded by: Chinese Ministry of Science and Technology 10.13039/501100002855
                Award ID: 2012CB911102
                Award ID: 2013ZX10001-005
                Funded by: Jilin Province 10.13039/501100003807
                Award ID: 20160101044JC
                Funded by: Health and Family Planning Commission of Jilin Province
                Award ID: 2013Z066
                Funded by: Key Laboratory of Molecular Virology, Jilin Province
                Award ID: 20102209
                RNA and RNA-protein complexes



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