The murine AIDS defective provirus acts as an insertional mutagen in its infected target B cells

Abstract

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 Sfpi1 (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.

Development of transgenic Xenopus laevis with a high C‐src gene expression

“…Proviral DNA contains strong promoters and enhancers in its LTR sequences that may directly or indirectly and over a relatively long distance influence expression of the oncogene. Rearranged forms of integrated proviral DNA containing only the right LTR (3Ј LTR) were found to act as strong mutagens, whereas the presence of the left LTR (5Ј LTR) in an intact provirus was found to quench the activity (see Nusse, 1986, for a review;Huang et al, 1995). RSV DNA detected in B 1 generation tadpoles involves the 3Ј-LTR including its enhancer that was proved by inverse PCR technique followed by sequencing.…”

Induction of B-Cell Lymphoma in BALB/c Nude Mice with an Ecotropic, B-Tropic Helper Virus Present in the Murine AIDS Virus Stock

“…Induction of clonal growth of lymphoid cells in C57BL/6 mice upon infection with a helper-free stock of defective MAIDS virus (8) does not exclude the possibility that the ecotropic helper virus plays an important role in inducing the malignant outgrowth of lymphoid cells. The frequent appearance of replication-competent helper virus in transplantable T-cell lines developed in mice infected with a helper-free stock (21) also suggested a possible role for it in leukemogenesis, such as insertional mutagenesis by the helper virus (9). The defective virus appears to cause the development of the early nonmalignant proliferation of B cells, while the helper virus develops the malignant B-or T-cell lymphoma much later in MAIDS; the transplantable B cells are different from the B cells proliferating in early MAIDS.…”