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 induc e marked expansion of its target cells, the majority of which belong t o the B-cell lineage. This expansion, which appears to be critical for the development of the immunodeficiency syndrome, is initially polycl onal but becomes oligoclonal late in the disease, suggesting the invol vement of a secondary genetic event(s) during this proliferation. To d etermine whether integration of the MAIDS defective provirus into part icular regions of the cellular genome contributes to this oligoclonal expansion, we searched for common provirus integration sites in enlarg ed lymphoid organs of MAIDS mice. We identified two common proviral in tegration sites, Dis-1 and Dis-2, which were occupied by a defective p rovirus at frequencies of 20 and 13%, respectively. Our analysis revea led that the Dis-1 region corresponds to the Sfpi1 (Spi-1, PU.1) locus , which maps on chromosome 2, and encodes a transcription factor. Inse rtion of the MAIDS defective provirus into this region led to a two- t o threefold increase in the expression of Sfpi1 RNA. The Dis-2 locus w as found to map to mouse chromosome 11, between Hox2 and Scya. It appe ars to be a novel locus probably harboring a gene involved in B-cell p roliferation. The present study indicates that the MAIDS defective pro virus can act as an insertional mutagen, thus contributing to the olig oclonal expansion of infected cells. The detection of two common provi ral integration sites, each of which targetted at a low frequency in d iseased organs, suggests that the deregulation of a unique gene throug h provirus insertion is essential for neither proliferation of infecte d B cells nor development of the immunodeficiency syndrome.