We seek to understand the mechanism(s) by which viruses alter the transcription of Class I genes and thereby impact on the capacity of the host to immunologically regulate the development of leukemia. Two sets of studies will deal with the mechanism(s) by which exogenous viruses such as Radiation leukemia virus (RadLV) deregulate Class I gene expression on infection and transformation of cells. A second set of studies described deal with endogenous viral sequences found inserted in the MHC of normal mice. The prototype virus for these studies is TLev-1, a complete retrovirus located in the TL region of the MHC. For the experimental plan, the proposal will deal with exogenous viruses which deregulate Class I gene expression. For exogenous viruses we wish to: (1) Determine the viral genetic information responsible for deregulation of Class I expression. (2) Identify the trans-acting factors mediating the RadLV effects on H-2 expression. (3) Identify and characterize the cis acting regulatory sequences in the H-2 region with which trans-acting factors interact. (4) Establish differences in cis regulatory sequences between the Dd gene which can be upregulated by RadLV infection) and the Dq (which cannot be upregulated by RadLV). (5) Determine why viral infection is associated with upregulation of murine class I expression, but viral-mediated transformation is associated with downregulation of class I gene of expression. (6) Understand alterations in DNA associated with RadLV transformation such as rearrangements and methylation changes. (7) Establish the frequency with which RadLV integrates in the MHC as compared to other sites.
Showing the most recent 10 out of 43 publications
