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Recombination between retroviral genomes occurs during infection of animals with avian tumor viruses, murine leukemia viruses and, more recently in humans, with human immunodeficiency virus (HIV). In animals exogenous viruses can recombine with endogenous retroviral sequences, giving rise to viruses with expanded host range properties. Mouse mammary tumor virus (MMTV) is a retrovirus that causes mammary gland adenocarcinomas in mice. The MMTV genome doesn't encode an oncogene, and causes mammary tumors by acting as an insertional mutagen through activation of the expression of cellular genes. Exogenous MMTV is passed from the milk of infected mothers to suckling babies, and infects cells of the immune system during its natural pathway from the gut to the mammary epithelial cells. Endogenous MMTVs have been found in the genomes of all laboratory and many feral mice. During the natural route of MMTV infection, exogenous virus can recombine with endogenous proviruses expressed in the infected tissues. We discovered that there are mammary tumors in C3H/HeN MMTV-infected females that carried recombinant MMTV as newly integrated copies. The recombinant virus resulted from recombination between exogenous MMTV and one of the endogenous MMTVs present in the genome of C3H/HeN mice. In this proposal, the cloning and sequencing of this recombinant MNTV from some of the mammary tumors are described, to determine the role of the different viral genes in the onset of mammary carcinogenesis. We will also examine the role of the immune system in the generation of recombinant virus with tumorigenic potential. The role of the host genetic background on the frequency and latency of mammary tumors associated with the recombinant virus will be analyzed. Transgenic mice carrying a new endogenous MMTV that lacks the gene encoding the superantigen protein encoded in the long terminal repeat of MMTV will be used to determine whether there is receptor interference in the MMTV system, that could lead to the selection of the new recombinant virus with an expanded host range. Thus, the results of these experiments will help us to better understand the mechanism of retroviral recombination leading to the generation of the pathogenic and tumorigenic viruses.
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