Origin of pathogenic determinants of recombinant murine leukemia viruses: analysis of Bxv-1-related xenotropic viruses from CWD mice

Abstract

The acquisition of U3 region sequences derived from the endogenous xenotropic provirus Bxv-1 appears to be an important step in the generation of leukemogenic recombinant viruses in AKR, HRS, C58, and some CWD mice. We report here that each of three CWD lymphomas produced infectious xenotropic murine leukemia virus related to Bxv-1. In Southern blot experiments, these proviruses hybridized to probes that were specific for the xenotropic envelope and Bxv-1 U3 region sequences. Nucleotide sequence analysis of a cloned CWD xenotropic provirus, CWM-S-5X, revealed that the envelope gene was closely related to but distinct from those of other known xenotropic viruses. In addition, the U3 region of CWM-S-5X contained a viral enhancer sequence that was identical to that found in MCF 247, a recombinant AKR virus that is thought to contain the Bxv-1 enhancer. Finally, restriction enzyme sites in the CWM-S-5X provirus were analogous to those reported within Bxv-1. These results establish that the virus progeny of Bxv-1 have the potential to donate pathogenic enhancer sequences to recombinant polytropic murine leukemia viruses. Interestingly, the three CWD polytropic viruses that were isolated from the same tumor cells that produced the Bxv-1-like viruses had not incorporated Bxv-1 sequences into the U3 region.

Structures of Endogenous Nonecotropic Murine Leukemia Virus (MLV) Long Terminal Repeats in Wild Mice: Implication for Evolution of MLVs

“…2). The type X-I proviruses include the previously identified proviruses Bxv1, NFS, and CWM, which encode infectious xenotropic virus (28,35). Bxv1 is also involved in the generation of oncogenic mink cell focus-forming (MCF) viruses in certain mice (23).…”

“…Although we have not studied the functions of the enhancerpromoter sequences in the wild-mouse proviruses, the U3 regions of retroviruses, in general, are intimately involved in viral replication and pathogenicity (24,33,35,36,44,53,57,64). Among all known nonecotropic proviruses, only the X-I group includes proviruses capable of yielding infectious virus (28,35,41).…”

The E47 transcription factor binds to the enhancer sequences of recombinant murine leukemia viruses and influences enhancer function

“…Moreover, this would explain why viruses with the CWM-T15 U3 region sequences induce lymphomas more rapidly than do chimeric viruses that contain the allelic U3 region sequences of the endogenous ecotropic viruses (27). The binding of E47 to the enhancer core region may also contribute to the selection of the pathogenic U3 region found in many AKR recombinants (20,21,31,33,44,45,52).…”

“…The U3 region of recombinants from AKR, C58, and HRS/J mice usually contains sequences derived from the endogenous xenotropic provirus Bxv-1 (17,26,31,44,45,52). A substantial proportion of recombinant viruses from CWD mice also contain Bxv-1 U3 region sequences, but as many as one-third of these viruses, including the CWM-T15 isolate, contain enhancer sequences that are probably inherited from an endogenous polytropic virus (33,34).…”

“…The pathogenicity of the CWM-T15 or Bxv-1-related U3 region sequences probably explains why recombinant viruses that acquire these sequences have a selective advantage in vivo. Because the sequences of the U3 regions of Bxv-1 and the endogenous ecotropic virus differ at about 70 positions, identification of the nucleotides that constitute the pathogenic determinant in the Bxv-1 U3 region would be difficult (26,33,52). However, the sequence of the U3 region of CWM-T15 differs from that of Emv-1 by only 5 bp, 3 bp of which are clustered immediately 3Ј of the core region of the viral enhancer (54).…”