Mechanism of selection of class II recombinant murine leukemia viruses in the highly leukemic strain CWD

Abstract

The development of spontaneous lymphomas in CWD mice is associated with the expression of endogenous ecotropic murine leukemia viruses (MuLV) and the formation of recombinant viruses. However, the pattern of substitution of nonecotropic sequences within the envelope genes of the CWD class II recombinant viruses differs from that seen in class I recombinant MuLVs of AKR, C58, and HRS mice. To determine how CWD host genes might influence the envelope gene structure of the recombinant viruses, we characterized the responses of these mice to two different types of exogenous MuLVs. Neonatal mice injected the HRS class I recombinant PTV-1 became infected and developed T-cell lymphomas more rapidly than controls did. The inoculation of CWD mice with the leukemogenic AKR ecotropic virus SL3-3 led to the formation of recombinant MuLVs with a novel genetic structure and class II-like envelope genes, although SL3-3 generates class I recombinants in other strains. These results suggest that the absence of class I recombinant MuLVs in CWD mice is not related to the restriction of the replication or oncogenicity of class I viruses or to the absence of an appropriate ecotropic virus that can generate class I recombinants. More likely, the genes of CWD mice that direct the formation or selection of class II recombinant viruses affect the process of recombination between the ecotropic and nonecotropic envelope gene sequences.

An increase in disease latency is associated with a host-dependent selection for recombinant murine leukemia viruses with substitutions in the p15E (TM) gene

“…About 100 bp of the polytropic virus sequences remained between the acquired endogenous ecotropic virus sequences and the beginning of the ecotropic 3' pl5E gene sequences that were inherited from CWN-T- 25. This suggests that the type I env phenotype is encoded by ecotropic plSE gene sequences that are located 5' of the BglII restriction site. In addition, this observation taken (8,22,32,35,36). together with the fact that only the SL3-3-induced recombinants retained ecotropic virus sequences in the 3' end of the pl5E gene implied that the origin of these sequences was influenced by characteristics of the ecotropic virus parent.…”

“…The classification is based on the observation that * Corresponding author. t Present address: Department of Microbiology, Dartmouth Medical School, Hanover,NH 03756. type I env recombinants retain ecotropic virus sequences in the 5' portion of the pl5E gene whereas the type II env recombinants do not (4,22,31,32,36). Type I env recombinant viruses are found in high leukemia strains HRS/J, AKR, and C58/J, whereas strain CWD, which is also highly susceptible to leukemia, and the NFS.akv strains produce type II env recombinants (8,11,22,28,32,35).…”

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.…”

“…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.…”