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Mechanism of Resistance to MMTV Induced Mammary Tumors

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Mouse Mammary Tumor Virus (MIMTV) is an exogenous milk-transmitted retrovirus that induces mammary gland tumors in some strains of laboratory mice. MMTV is carried from the gut of suckling pups to the mammary glands by lymphocytes. Susceptibility to exogenous MMTV infection and subsequent mammary tumorigenesis differs drastically, from absolute resistance to high susceptibility. For example, mice of the C3H/HeN or BALB/cJ strains are highly susceptible, whereas mice of the I/LnJ strain are highly resistant. We found that IJLnJ mice neonatally infected with MMTV produced avirulent virus particles, as they were coated with anti-virus antibodies of IgG2a isotype. The same antibodies were found in the sera of infected IJLnJ mice and were capable of neutralizing MMTV infection. The antibodies were reactive against env and gag gene products. Imrnunoglobulin isotope distribution was found to be normal in sera of uninfected I/LnJ mice, and immunization with virion proteins did not cause a bias production of anti-virus antibodies towards IgG2a isotype. Furthermore, JILnJ mice infected with another retrovirus, murine leukemia virus, also produced anti-virus neutralizing antibodies of IgG2a isotype specific for Env. Thus, it appears that the production of anti-virus antibodies of IgG2 isotype is a specialized response to retrovirus infection in I/LnJ mice. We established that a single gene (virus infectivity controller or vic) determines the production of these neutralizing antibodies in MMTV-infected JILnJ mice. The vic' about (resistant) allele found in JJLnJ mice is recessive to the vicS (susceptible) allele in C3WHeN or BALB/cJ mice. We plan to investigate the molecular mechanism of anti-virus antibody production and clone the gene conferring the resistant phenotype in I/LnJ mice.

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