Mouse mammary tumor virus (MMTV), a retrovirus that exploits the immune system. Genetics of susceptibility to MMTV infection

All animals, including humans, show differential susceptibility to infection with viruses. Study of the genetics of susceptibility or resistance to specific pathogens is most easily studied in inbred mice. We have been using mouse mammary tumor virus (MMTV), a retrovirus that causes mammary tumors in mice, to study virus/host interactions. These studies have focused on understanding the mechanisms that determine genetic susceptibility to MMTV-induced mammary tumors, the regulation of virus gene expression in vivo and how the virus is transmitted between different cell types. We have found that some endogenous MMTVs are only expressed in lymphoid tissue and that a single base pair change in the long terminal repeat of MMTV determines whether the virus is expressed in mammary gland. This expression in lymphoid cells is necessary for the infectious cycle of MMTV, and both T and B cells express and shed MMTV. Infected lymphocytes are required not only for the initial introduction of MMTV to the mammary gland, but also for virus spread at later times. Without this virus spread, mammary tumorigenesis is dramatically reduced. Mammary tumor incidence is also affected by the genetic background of the mouse and at least one gene that affects infection of both lymphocytes and mammary cells has not yet been identified. The results obtained from these studies will greatly increase our understanding of the genetic mechanisms that viruses use to infect their hosts and how genetic resistance to such viruses in the hosts occurs.

Superantígenos y retrovirus del tumor mamario murino / Superantigens and murine mammary tumor retrovirus

Hosts and their pathogens have co-evolved for millions of years, developing multiple and intimate interactions. Vertebrates have evolved a very complex immune system which pathogens have often been able to circumvent, in some cases even managing to appropriate some of its components for their own purpose. Among the pathogens which do use components of the immune system to survive and propagate, those coding for the expression of superantigens (SAgs) are now under intense scrutiny. Investigations concerning one of these pathogens, the mouse mammary tumor virus (MMTV), led to the understanding of how the expression of such components is a critical step in their life cycle. A number of milk-borne exogenous MMTV infect mice shortly after birth and, when expressed, produce superantigens. Herein, we describe the biological effects of new variants of MMTV. Two of these, BALB14 and BALB2 encoding SAgs with V beta 14+ and V beta 2+ specificities, respectively, were present in BALB/c mice of our colony (BALB/cT); a third variant, termed MMTV LA, originated in (BALB/cTxAKR)F1 mice from recombination between BALB 14 and Mtv-7 endogenous provirus. The recombinant LA virus induces the deletion of V beta 6+ and V beta 8.1+ T cells as a consequence of the acquisition of SAg hypervariable coding region of Mtv-7. The SAg encoded by MMTV LA strongly stimulates cognate T cells in vivo leading to a very effective amplification of lymphoid cells in BALB/c mice, correlating with a high incidence of mammary tumors. These results suggest that the presence of non-productive endogenous proviruses--generally considered to confer a selective advantage to the host by protecting it from infection with exogenous MMTVs encoding cross-reactive SAgs--could also be advantageous for the pathogen by increasing its variability, thus broadening the host range and allowing the expansion of highly tumorigenic variants.

Mouse mammary tumor virus (MMTV), a retrovirus that exploits the immune system. Genetics of susceptibility to MMTV infection

All animals, including humans, show differential susceptibility to infection with viruses. Study of the genetics of susceptibility or resistance to specific pathogens is most easily studied in inbred mice. We have been using mouse mammary tumor virus (MMTV), a retrovirus that causes mammary tumors in mice, to study virus/host interactions. These studies have focused on understanding the mechanisms that determine genetic susceptibility to MMTV-induced mammary tumors, the regulation of virus gene expression in vivo and how the virus is transmitted between different cell types. We have found that some endogenous MMTVs are only expressed in lymphoid tissue and that a single base pair change in the long terminal repeat of MMTV determines whether the virus is expressed in mammary gland. This expression in lymphoid cells is necessary for the infectious cycle of MMTV, and both T and B cells express and shed MMTV. Infected lymphocytes are required not only for the initial introduction of MMTV to the mammary gland, but also for virus spread at later times. Without this virus spread, mammary tumorigenesis is dramatically reduced. Mammary tumor incidence is also affected by the genetic background of the mouse and at least one gene that affects infection of both lymphocytes and mammary cells has not yet been identified. The results obtained from these studies will greatly increase our understanding of the genetic mechanisms that viruses use to infect their hosts and how genetic resistance to such viruses in the hosts occurs.