Host resistance and viral transcription as determinants of MMTV tumorigenesis

Mouse mammary tumor virus (MMTV) is an oncogenic retrovirus that causes mammary tumors in susceptible mice within 6 to 9 months of infection. Type B leukemogenic virus (TBLV) is a variant of MMTV that induces thymic lymphomas in mice, instead of mammary tumors, with a shorter latency. Exogenous MMTV has a complicated life cycle involving milk-borne virus transmission and tissue type and differentiation-specific regulation of viral transcription. Most inbred mouse strains also harbor endogenous MMTV proviruses (Mtvs) in their germline that are inherited according to Mendelian rules and are usually not associated with mammary tumorigenesis. This thesis reports studies on the intricate relationship of MMTV with its host by demonstrating that the outcome of MMTV infection is influenced by both the composition of viral transcriptional elements and by host genetics. This is the first demonstration that the absence of negative regulation of viral transcription and presence of a T-cell specific enhancer in lymphoid cells converts a mammotropic MMTV to a lymphotropic virus. Interestingly, the endogenous Mtv loci in the BALB/cJ mouse genome are required for susceptibility to infection and tumorigenesis by both MMTV and TBLV. A BALB/cJ congenic mouse strain lacking endogenous Mtvs (BALB/Mtv-null) is highly resistant to both MMTV and TBLV. The resistance is not mediated by the production of MMTV-specific neutralizing antibodies in the BALB/Mtv-null strain. However, cell-mediated immune response directed against MMTV-infected cells might contribute towards the tumor resistance phenotype. The BALB/Mtv-null mice also are resistant to oral infection with the bacterial pathogen Vibrio cholerae compared to BALB/cJ mice, and this resistance to V. cholerae correlates with the absence of endogenous Mtvs. Thus, the BALB/Mtv-null mice demonstrate a novel mode of resistance to multiple pathogens that appears to be linked to expression of MMTV genes. These data support a role for endogenous Mtvs in determining susceptibility to multiple pathogens.