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Fv-4 resistance gene: a truncated endogenous murine leukemia virus with ecotropic interference properties
1Laboratory of Experimental Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Abstract:
Fv-4 is a mouse gene which controls susceptibility to infection by ecotropic murine leukemia virus (MuLV). We previously cloned part of an endogenous MuLV associated with the resistance allele of the Fv-4 gene (Fv-4r). In this report, we describe an extended clone of the Fv-4r allele consisting of a 17-kilobase DNA fragment containing the retroviral sequence and its 5'-flanking sequence. The new DNA clone contains a truncated MuLV with delta pol-env-long terminal repeat sequences but no other MuLV-reactive sequence within 13 kilobases upstream of the truncated MuLV. Transfection of this clone into mouse cells led to transcription of Fv-4 env mRNA, expression of the Fv-4r-specific MuLV envelope protein, and resistance to infection with ecotropic MuLV but not amphotropic and dualtropic MuLVs. Restriction of ecotropic viruses appears to occur at or before viral cDNA synthesis. This result is consistent with a model of receptor interference for Fv-4 restriction. Our data also suggest that the 5' non-MuLV sequence is important for biological function, since a DNA clone which lacks most of the 5'-flanking sequence did not efficiently confer the resistance phenotype.
Insights
The Fv-4 gene confers resistance to ecotropic murine leukemia virus (MuLV) infection. Its Fv-4r allele functions via an envelope protein, blocking viral entry and replication.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- The Fv-4 gene in mice controls susceptibility to ecotropic murine leukemia virus (MuLV).
- Previous work identified an endogenous MuLV linked to the Fv-4 resistance allele (Fv-4r).
Purpose of the Study:
- To characterize an extended DNA clone of the Fv-4r allele.
- To investigate the molecular mechanisms underlying Fv-4 mediated resistance to MuLV infection.
Main Methods:
- Cloning and sequencing of a 17-kilobase DNA fragment of the Fv-4r allele.
- Transfection of the DNA clone into mouse cells.
- Analysis of viral mRNA transcription and protein expression.
- Testing resistance to infection by different MuLV strains.
Main Results:
- The extended clone contained a truncated MuLV with specific sequence deletions.
- Transfected cells expressed Fv-4 env mRNA and the Fv-4r-specific envelope protein.
- Cells exhibited resistance to ecotropic MuLV but not amphotropic or dualtropic MuLVs.
- Resistance mechanism appears to involve receptor interference at or before viral cDNA synthesis.
Conclusions:
- The Fv-4r allele confers resistance to ecotropic MuLV via its envelope protein.
- The 5'-flanking non-MuLV sequence is crucial for the resistance phenotype.
- Fv-4 restriction likely operates through a receptor interference model.