Retroviruses are known to be involved in the induction of malignancies in many species. The oncogenicity of these viruses is thought to require the expression of an oncogene which either is transcribed as part of the viral genome or the cellular homology mutated by the insertion of viral DNA. In the latter mechanism of retrovirus-induced oncogenesis random integration of viral DNA in the host genome is proposed to occur at or near an oncogene resulting in alter expression. Analysis of the replication of baboon endogenous virus (BEV) in somatic cell hybrids formed between human and hamster cells revealed a single locus on human chromosome 6 was required. This locus was shown to be required for integration of the virus, because all viral DNA sequences segregated with this chromosome. Recent data developed in this laboratory has identified a specific sequence which is a high affinity target for BEV DNA integration. This target sequence is found associated with most BEV proviruses in human cells. In the proposed study the sequence specific integration of this virus in human cells will be examined. The target sequence recognized by the virus will be cloned and sequenced and a consensus target sequence obtained from the analysis of many independent integration events. Once cloned the arrangement of the target sequence at the BEVI locus will be determined and its distribution among human chromosomes and DNA from other species determined. In addition, those viral and host-specific functions other than the target sequence involved in sequence specific integration will be determined. Furthermore, the feasibility of BEV as an eucaryotic cloning vector will be evaluated. Finally, since the BEVI locus and the HL-A locus map at similar locations on the short arm of chromosome 6, the possible relationship between these two loci will be explored.
| Huang, L H; Silberman, J; Rothschild, H et al. (1989) Replication of baboon endogenous virus in human cells. Kinetics of DNA synthesis and integration. J Biol Chem 264:8811-4 |
| Wilson, A F; Cohen, J C (1988) Hypotheses for testing deviations from random integration: evidence for nonrandom retroviral integration. Genomics 3:137-42 |
