![]() ![]() An analysis to determine the step at which ZAP blocked virus infection revealed that in ZAP-expressing cells, reverse transcription and nuclear entry of the viral DNA were normal but the production of viral RNA in the cytoplasm was inhibited ( 11). The overexpression of ZAP rendered cells 30-fold more resistant to viral infection. The zinc finger antiviral protein (ZAP) was originally recovered from a screen for genes conferring resistance to the infection of cells by Moloney murine leukemia virus (MLV) ( 11). Disruption of the second and fourth zinc fingers abolished ZAP's activity, whereas disruption of the first and third fingers just slightly lowered its activity. The CCCH zinc finger motifs of ZAP play important roles in RNA binding and antiviral activity. We provide evidence that ZAP directly binds to the active but not the inactive fragments. ![]() Any further deletion of this fragment resulted in significantly lower activity. This led to the identification of a fragment of 653 nucleotides. The fragment of SIN that displayed the highest destabilizing activity was further analyzed by deletion mutagenesis for the minimal sequence that retained the activity. The sensitive sequence in MLV was mapped to the 3′ long terminal repeat the sensitive sequences in SIN were mapped to multiple fragments. The viral sequences were cloned into a luciferase reporter and analyzed for the ability to mediate ZAP-dependent destabilization of the reporter. For this report, we mapped the viral sequences that are sensitive to ZAP inhibition. It specifically inhibits the replication of Moloney murine leukemia virus (MLV) and Sindbis virus (SIN) by preventing the accumulation of viral RNA in the cytoplasm. The zinc finger antiviral protein (ZAP) is a recently isolated host antiviral factor.
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