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J. Virol. doi:10.1128/JVI.01538-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

MUTATION IN THE GLYCOSYLATED GAG PROTEIN OF MURINE LEUKEMIA VIRUS RESULTS IN REDUCED IN VIVO INFECTIVITY AND A NOVEL DEFECT IN VIRAL BUDDING OR RELEASE

Department of Molecular Biology and Biochemistry, and Cancer Research Institute, University of California, Irvine, CA 92697-3905

^* To whom correspondence should be addressed. Email: hyfan{at}uci.edu.

	Abstract

All gammaretroviruses, including murine leukemia viruses, feline leukemia viruses and gibbon-ape leukemia virus encode an alternate glycosylated form of Gag polyprotein (glyco-gag or gPr80^gag) in addition to the polyprotein precursor for the viral capsid proteins (Pr65^gag). gPr80^gag is translated from an upstream in-frame CUG initiation codon compared to the AUG for Pr65^gag. The role of glyco-gag in MuLV replication has been unclear, since gPr80^gag-negative M-MuLV mutants are replication-competent in vitro and pathogenic in vivo. However, reversion to wild-type is frequently observed in vivo. In these experiments, in vivo inoculation of a gPr80^gag mutant Ab-X-M-MuLV showed substantially lower (2 logs) initial infectivity in newborn NIH Swiss mice compared to wild-type virus, and revertants to wild-type could be detected by PCR cloning and DNA sequencing as early as 15 days post-infection. Atomic force microscopy (AFM) of Ab-X-M-MuLV - infected producer cells, or of the PA317 amphotropic MuLV-based vector packaging line (also gPr80^gag-negative) revealed the presence of tube-like viral structures on the cell surface. In contrast, wild-type virus-infected cells showed the typical spherical 145 nm particles observed previously. Expression of gPr80^gag in PA317 cells converted the tube-like structures to typical spherical particles. PA317 cells expressing gPr80^gag produced 5-10-fold more infectious vector or viral particles as well. Metabolic labeling studies indicated that this reflected enhanced virus particle release rather than increased viral protein synthesis. These results indicate that gPr80^gag is important for M-MuLV replication in vivo and in vitro, and that the protein may be involved in a late step in viral budding or release.

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