The murine AIDS defective provirus acts as an insertional mutagen in its infected target B cells.
In susceptible mice, the murine AIDS (MAIDS) defective virus can induce marked expansion of its target cells, the majority of which belong to the B-cell lineage. This expansion, which appears to be critical for the development of the immunodeficiency syndrome, is initially polyclonal but becomes oligoclonal late in the disease, suggesting the involvement of a secondary genetic event(s) during this proliferation. To determine whether integration of the MAIDS defective provirus into particular regions of the cellular genome contributes to this oligoclonal expansion, we searched for common provirus integration sites in enlarged lymphoid organs of MAIDS mice. We identified two common proviral integration sites, Dis-1 and Dis-2, which were occupied by a defective provirus at frequencies of 20 and 13%, respectively. Our analysis revealed that the Dis-1 region corresponds to the Sfpil1 (Spi-1, PU.1) locus, which maps on chromosome 2, and encodes a transcription factor. Insertion of the MAIDS defective provirus into this region led to a two- to threefold increase in the expression of Sfpi1 RNA. The Dis-2 locus was found to map to mouse chromosome 11, between Hox2 and Scya. It appears to be a novel locus probably harboring a gene involved in B-cell proliferation. The present study indicates that the MAIDS defective provirus can act as an insertional mutagen, thus contributing to the oligoclonal expansion of infected cells. The detection of two common proviral integration sites, each of which targetted at a low frequency in diseased organs, suggests that the deregulation of a unique gene through provirus insertion is essential for neither proliferation of infected B cells nor development of the immunodeficiency syndrome.
Huang
M
M
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Québec, Canada.
Takac
M
M
Kozak
C A
CA
Jolicoeur
P
P
D000818:Animals; D001402:B-Lymphocytes / Q000821:virology; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D003673:Defective Viruses / Q000235:genetics*; D009052:Leukemia Virus, Murine / Q000235:genetics*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016183:Murine Acquired Immunodeficiency Syndrome / Q000821:virology*; D009153:Mutagens; D011533:Proviruses / Q000235:genetics*; D012367:RNA, Viral / Q000032:analysis; D012091:Repetitive Sequences, Nucleic Acid; D016662:Virus Integration
D009153:Mutagens; D012367:RNA, Viral