Pathogenic determinants in the U3 region of recombinant murine leukemia viruses isolated from CWD and HRS/J mice

Abstract

Recombinant murine leukemia viruses (MuLVs) from high-leukemia-incidence mouse strains typically acquire pathogenic U3 region sequences from the genome of the endogenous xenotropic virus, Bxv-1. However, a recombinant virus isolated from a leukemic HRS/J mouse and another from a CWD mouse contained U3 regions that lacked genetic markers of Bxv-1. The U3 regions of both recombinants were derived from the endogenous ecotropic virus Env-1 and had retained a single enhancer element. However, compared with that of Emv-1, the U3 region of each of the recombinant viruses contained five nucleotide substitutions, one of which was shared. To determine the biological significance of these substitutions, chimeric ecotropic viruses that contained the U3 region from one of the two recombinant viruses or from Emv-1 were injected into NIH Swiss mice. All three of the chimeric ecotropic viruses were leukemogenic following a long latency. Despite the presence of an enhancer core motif that is known to contribute to the leukemogenicity of the AKR MuLV SL3-3, the HRS/J virus U3 region induced lymphomas only slightly more rapidly than the allelic Emv-1 sequences. The chimeric virus with the U3 region of the CWD recombinant caused lymphomas more frequently and more rapidly than either of the other two viruses. The results support the hypothesis that one or more of the five nucleotide substitutions in the U3 regions of the recombinants contribute to viral pathogenicity. Comparison of DNA sequences suggests that the pathogenicity of the CWD virus U3 region was related to a sequence motif that is shared with Bxv-1 and is recognized by the basic helix-loop-helix class of transcription factors.