Gao G, Guo X, Bick MJ, MacDonald M, Rice C, Goff SP; HIV DRP Symposium Antiviral Drug Resistance (4th: 2003: Chantilly, Va.).
Program Abstr HIV DRP Symp Antivir Drug Resist. 2003 Dec 7-10; 4: Abstract no. 16.
Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080, China
To identify novel antiviral activities, we screened mammalian cDNA libraries for genes that prevent infection by a genetically marked MuLV vector. Virus-resistant cells were selected from pools of transduced clones, and an active antiviral cDNA was recovered from one such line. Expression of the gene caused a profound and specific loss of viral mRNAs from the cytoplasm without affecting the levels of nuclear mRNAs. The gene encodes a CCCH-type zinc finger protein designated ZAP. ZAP contained four predicted zinc finger motifs near the amino terminus, and a protein destabilization motif near the carboxyterminus. Mutational analyses showed that cysteine residues in the second and fourth of the zinc finger motifs of ZAP were critical for the antiviral activity. A region near the 3' end of the Moloney MuLV RNA was identified as necessary and sufficient to provide sensitivity to ZAP and to target mRNAs for loss. ZAP was tested for its ability to inhibit viruses from other families and was shown to potently inhibits the replication of multiple members of the alphavirus genus, including Sindbis, Semliki Forest, Ross River, and Venezuelan equine encephalitis viruses. However, expression of ZAP did not induce a universal antiviral state: some viruses, including HIV-1, vesicular stomatitis virus, poliovirus, and herpes simplex virus type 1, replicated to normal levels in ZAP-expressing cells. ZAP expression inhibited Sindbis virus replication after virus penetration and entry, but before the amplification of newly synthesized plus strand genomic RNA. The findings suggest the existence of a previously unknown machinery for inhibition of virus replication, targeting a novel step in viral gene expression.
Publication Types:
Keywords:
- Alphavirus
- Amino Acid Motifs
- Antiviral Agents
- Gene Library
- Genes, Viral
- Protein Transport
- Proteins
- RNA, Messenger
- RNA, Viral
- Sindbis Virus
- Vesicular stomatitis Indiana virus
- Virus Replication
- Zinc Fingers
- genetics
- virology
Other ID:
UI: 102268441
From Meeting Abstracts