Zinc-Finger Antiviral Protein Inhibits XMRV Infection

Abstract

Background The zinc-finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses, including Moloney murine leukemia virus (MoMLV), HIV-1, and certain alphaviruses and filoviruses. ZAP binds to specific viral mRNAs and recruits cellular mRNA degradation machinery to degrade the target RNA. The common features of ZAP-responsive RNA sequences remain elusive and thus whether a virus is susceptible to ZAP can only be determined experimentally. Xenotropic murine leukemia virus-related virus (XMRV) is a recently identified γ-retrovirus that was originally thought to be involved in prostate cancer and chronic fatigue syndrome but recently proved to be a laboratory artefact. Nonetheless, XMRV as a new retrovirus has been extensively studied. Since XMRV and MoMLV share only 67.9% sequence identity in the 3′UTRs, which is the target sequence of ZAP in MoMLV, whether XMRV is susceptible to ZAP remains to be determined. Findings We constructed an XMRV-luc vector, in which the coding sequences of Gag-Pol and part of Env were replaced with luciferase-coding sequence. Overexpression of ZAP potently inhibited the expression of XMRV-luc in a ZAP expression-level-dependent manner, while downregulation of endogenous ZAP rendered cells more sensitive to infection. Furthermore, ZAP inhibited the spreading of replication-competent XMRV. Consistent with the previously reported mechanisms by which ZAP inhibits viral infection, ZAP significantly inhibited the accumulation of XMRV-luc mRNA in the cytoplasm. The ZAP-responsive element in XMRV mRNA was mapped to the 3′UTR. Conclusions ZAP inhibits XMRV replication by preventing the accumulation of viral mRNA in the cytoplasm. Documentation of ZAP inhibiting XMRV helps to broaden the spectrum of ZAP's antiviral activity. Comparison of the target sequences of ZAP in XMRV and MoMLV helps to better understand the features of ZAP-responsive elements.

Zinc finger antiviral protein inhibits coxsackievirus B3 virus replication and protects against viral myocarditis

“…5 and 6). Additionally, we also evaluated whether ZAP inhibited CVB3 replication by activating RIG-I signaling and found knockdown of RIG-I in HeLa cells did not influence the antiviral effect of ZAP (data not shown), which is consistent with report of ZAP effect against XMRV (Wang, Tu et al, 2012). We also failed to detect any increase of IFN expression after overexpression of ZAP in vivo (Fig.…”

“…ZAP has been reported to suppress the replication of positive-stranded RNA viruses (Alphavirus and Flavivirus of Togaviridae), negativestranded RNA viruses (Filoviridae such as EBOV and MARV) and retroviruses (Retroviridae such as HIV, HBV and MMLV) in human cell lines. However, ZAP did not exhibit a broad-spectrum antiviral state in some viruses, including VSV, poliovirus and yellow fever virus, replicated to normal levels in ZAP-expressing cells (Muller, Moller et al, 2007;Zhu, Chen et al, 2011;Wang, Tu et al, 2012;Xuan, Liu et al, 2012;Mao, Nie et al, 2013;Chen, Dai et al, 2015). CVB3 and poliovirus are members of the positive-stranded RNA virus family picornaviridae, effect of ZAP on CVB3 replication has never been reported.…”

“…Previous studies have demonstrated that ZAP prevents the accumulation of viral RNA by targeting specific sequences mostly found in 3 0 or 5 0 untranslated region (UTR) of viral RNA (Zhu, Chen et al, 2011;Wang, Tu et al, 2012). To identify the target sequences of ZAP in CVB3 genome, the 3 0 UTR and 5 0 UTR of CVB3 were cloned into the pGL3-luciferase reporter plasmid respectively (Fig.…”

“…Human ZAP has a long and a short isoform (hZAP-L and -S) resulting from different mRNA splicing and both of them are reported to restrict replication of RNA viruses such as alphaviruses, floviruses and retroviruses including human immunodeficiency virus (HIV), hepatitis B virus (HBV), xenotropic murine leukemia virus-related virus (XMRV). However, ZAP does not exhibit antiviral effect commonly to all viruses, some viruses such as vesicular stomatitis virus (VSV), poliovirus and yellow fever virus, replicate normally in ZAP-overexpressed cells (Muller, Moller et al, 2007;Zhu, Chen et al, 2011;Wang, Tu et al, 2012;Xuan, Liu et al, 2012;Mao, Nie et al, 2013;Chen, Dai et al, 2015). ZAP is demonstrated to exert its antiviral effect by binding to viral RNA through its CCCH zinc finger motif and recruiting host RNA exosome or cellular decapping complex to degrade viral RNA in the cytoplasm (Guo, Carroll et al, 2004;Lee, Komano et al, 2013).…”

“…ZAP is demonstrated to exert its antiviral effect by binding to viral RNA through its CCCH zinc finger motif and recruiting host RNA exosome or cellular decapping complex to degrade viral RNA in the cytoplasm (Guo, Carroll et al, 2004;Lee, Komano et al, 2013). The ZAPresponsive elements (ZREs) vary among viral RNAs (Guo, Carroll et al, 2004;Zhu, Chen et al, 2011;Wang, Tu et al, 2012). Since there is no report of the effect of ZAP on enteroviruses infection and almost no biological function of ZAP has been confirmed in animal models of viral infection, it is of great interest to explore the possible antiviral function of ZAP on CVB3 and role of ZAP in the development of CVB3-induced acute viral myocarditis (VMC).…”