A key step in the pathogenesis of leukemia associated with ecotropic retrovirus infection in mice is altered regulation of myc or other proto-oncogenes caused by adjacent integration of an MCF provirus (12, 30, 57). MCF viruses are the product of recombination between the genome of the inciting ecotropic virus and host sequences derived from defective endogenous proviruses (27-29, 79). In studies of virus receptor function in human 293 cells, we observed that cells exposed to MCF247 virus acquired 20-40-fold more proviruses/cell than cells exposed to closely related retroviruses that are not pathogenic (85). Our studies have identified two possible explanations for this observation: 1) The receptor binding affinity of the MCF247 env gp is significantly lower than other viruses (Ka >100 nM) and therefore a substantially higher level of env gp expression is required before additional infection is blocked by receptor down regulation. 2) MCF247 viruses are uniquely suited to gain entry into certain cells through an alternative mechanism that is not dependent on direct binding to a cellular receptor. By this route, infection is triggered by binding of the MCF247 virus env gp to the env gp of an ecotropic virus located in a complex with its receptor on the surface membrane of the target cell (85). This mechanism, termed """"""""trans-activation"""""""" is not down regulated by expression of the MCF247 virus env gp and therefore its activity is independent of the number of prior infections (and provirus insertions). We propose the combined use of both receptor and trans-activation-dependent mechanisms provides the MCF247 virus with a selective advantage over other recombinant viruses that are created during ongoing ecotropic virus replication and may explain, in part, why MCF247 virus is highly leukemogenic. In addition, we observe that trans-activation is the sole mechanism of infection by FeLV-T (8), a recombinant feline retrovirus associated with profound immunodeficiency caused by massive provirus accumulation and apoptosis in T cells (25, 66). The behavior of FeLV-T and MCF247 viruses suggests that cooperative interactions between recombinant and inciting viruses may contribute to the content and properties of the quasi-species in an infected host. To date, our studies of trans-activation have been largely limited to FeLV-T and MCF247 viruses in vitro.
Our specific aims are to: ? 1. Determine if susceptibility to trans-activation is a common property of pathogenic MCF viruses. ? 2. Develop an in vitro system to investigate the mechanism of trans-activation. ? 3. Assess the contribution of trans-activation to the pathogenesis of retrovirus-induced leukemia in mice. ? ? ?
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