PATHOGENIC DETERMINANTS IN THE U3 REGION OF RECOMBINANT MURINE LEUKEMIA VIRUSES ISOLATED FROM CWD AND HRS J MICE/

Recombinant murine leukemia viruses (MuLVs) from high-leukemia-inciden ce mouse strains typically acquire pathogenic U3 region sequences from the genome of the endogenous xenotropic virus, Bxv-1, However, a reco mbinant virus isolated from a leukemic HRS/J mouse and another from a CWD mouse contained U3 regions that lacked genetic markers of Bxv-1 Th e U3 regions of both recombinants were derived from the endogenous eco tropic virus Emv-1 and had retained a single enhancer element. However , compared with that of Emv-1, the U3 region of each of the recombinan t viruses contained five nucleotide substitutions, one of which was sh ared. To determine the biological significance of these substitutions, chimeric ecotropic viruses that contained the U3 region from one of t he two recombinant viruses or from Emv-1 were injected into NIH Swiss mice. All three of the chimeric ecotropic viruses were leukemogenic fo llowing a long latency. Despite the presence of an enhancer core motif that is known to contribute to the leukemogenicity of the AKR MuLV SL 3-3, the HRS/J virus U3 region induced lymphomas only slightly more ra pidly than the allelic Emv-1 sequences. The chimeric virus with the U3 region of the CWD recombinant caused lymphomas more frequently and mo re rapidly than either of the other two viruses. The results support t he 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 CW D 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 transcr iption factors.