A host gene regulates the structure of the transmembrane envelope protein of murine leukemia viruses.

Abstract

Heterogeneity in the structure of the envelope proteins has been observed in many human and animal retroviruses and may influence pathogenicity. However, the biological significance of this heterogeneity and the mechanisms by which it is generated are poorly understood. We have studied a mouse model in which the envelope gene structure of lymphoma-associated viruses appears to be controlled by a single host gene. The inoculation of HRS and CWD mice with a leukemogenic murine leukemia virus (MuLV) results in recombination between the injected virus and envelope gene sequences of endogenous retroviruses. The genomes of HRS (class I) env recombinants and CWD (class II) env recombinants differ in the sequences encoding the NH2-terminal portion of the transmembrane envelope protein (TM). We have shown that an HRS gene linked to the MHC on chromosome 17 mediates a dominant selection for recombinant retroviruses with the class I envelope gene structure. CBA mice, which share the H-2k haplotype with HRS, also carry the dominant allele at this locus. This system provides a useful model for studies of host factors involved in the selection of specific variants of pathogenic retroviruses.

The MouseH-2ARegion Influences the Envelope Gene Structure of Tumor-Associated Murine Leukemia Viruses

“…We had previously shown that the presence of type I or type II recombinants within lymphoma cells is influenced by a host gene located on mouse chromosome 17. In these experiments, the injection of the ecotropic SL3-3 MuLV induced tumors and type I recombinants in HRS/J mice, whereas tumors from injected CWD mice contained type II recombinants (6,32,37). The type I-forming phenotype (TI) of HRS/J mice was dominant with respect to the type II-forming phenotype (TII) of CWD mice and segregated with restriction fragment length polymorphisms on chromosome 17 which are located within the H-2 locus, the mouse major histocompatibility complex.…”

“…Animals of these strains express early in life endogenous ecotropic MuLVs that subsequently acquire pathogenic sequences by recombination with endogenous polytropic and xenotropic viruses. Similarly, the injection of exogenous ecotropic MuLVs, such as SL3-3, into these or other susceptible strains induces leukemias and the formation of envelope gene recombinants (6,10,31). The recombinants typically incorporate 5Ј envelope gene sequences from one or more of the 20 or so endogenous polytropic viruses.…”

“…The MuLV envelope gene (env) encodes a common precursor protein, gp85, that is cleaved to yield two products, the mature gp70 and the minor envelope protein, TM or p15E (12,43). The 5Ј portion of the gp70 gene of the recombinant viruses is composed of sequences inherited from the endogenous polytropic viruses, but the 5Ј portion of the p15E gene may be de-rived from either the ecotropic or polytropic virus parent (6,23,32,35,37). Recombinants in which the 5Ј p15E gene contains ecotropic virus sequences are classified as type I recombinants, whereas those that acquire the allelic polytropic virus sequences in this region are designated type II recombinants ( Fig.…”

“…The earlier genetic studies of the TI gene of HRS/J and CBA/J mice and the observation that all H-2 k strains exhibited the TI phenotype suggested that the TI gene(s) may be located within or near the H-2 locus (6,23,32,37). To test if the H-2 genes regulate the TI or TII phenotype, we injected a modified ecotropic SL3-3 MuLV into C57BL/10 (B10) strains that were congenic at H-2.…”

Tissue Distribution and Timing of Appearance of Polytropic Envelope Recombinants during Infection with SL3-3 Murine Leukemia Virus or Its Weakly Pathogenic SL3ΔMyb5 Mutant

“…The structure of the polytropic recombinant generated during SL3 infection is dependent on the mouse strain serving as host and is influenced by host factors. In HRS/J and CBA/J mice, for example, the dominant selection for type I env recombinants is controlled by a single host gene that is not an endogenous provirus but resides within the major histocompatibility complex (4,10,(12)(13)(14). Both type I and type II env recombinants arise during SL3 infection NIH/Swiss mice (12,14), the strain examined in the present study.…”