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.

En busca de secuencias retrovirales relacionadas con el cáncer de mama humano / Searching for retroviral sequences related to human breast cancer

The participation of viruses in mammary carcinogenesis has been largely studied in animals. A model similar to the mouse mammary tumor virus (MMTV) was previously proposed. Several lines of research supported the participation of MMTV in human breast cancer, but these evidences were contradicted when further research was performed. One major issue was the presence of human endogenous retroviral sequences that confounded results reporting MMTV-like sequences in human breast cancer. To overcome this problem we selected a 660 bp sequence of the MMTV env gene with low homology to endogenous sequences and search for a sequence to it using the polymerase chain reaction (PCR). The sequence was found in 38 of the human breast cancers and in 2 of the normal breasts studied. The sequence was not present in tumors from other organs. It was 90-98 homologous to MMTV and only 18 to human endogenous retrovirus (HERV) K-10. It was also detected in some of the positive tumors by Southern blot hybridization using one of the cloned 660 bp as a probe. Using reverse transcriptase PCR, it was possible to demonstrate that the 660 bp sequence is expressed in the majority of the tumors. Also, preliminary experiments revealed that sequences related to the LTR and gag genes of MMTV were present in the DNA of breast tumors. The origin of the MMTV-like sequences in tumor DNA could be the result of integrated MMTV-like sequences derived from a human mammary virus or may represent unknown endogenous sequences that can only be detected in breast tumors.

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.

Visión retrospectiva de la relación entre los retrovirus y el cáncer / Retrovirus and cancer revisited

The discovery of RNA oncoviruses dates back to 1911 when Rous isolated the avian virus which is the cause of the sarcoma which bears his name and to 1936 when Bittner related the "milk factor" to the development of murine mammary cancer. During the 50s, the successive descriptions of virus-induced sarcoma-leukemias in mice led to the oncogene theory and gradually to the postulation of a viral origin of cancer. The discovery of the reverse transcriptase in 1970 led to the establishment of the Retroviridae family including both onco and lentiviruses. The decade of the 80s was marked by three fundamental discoveries which altered the concept of oncovirus: 1) oncogenes became established as part of the cellular genome converting retroviruses into occasional vectors of the oncogene; 2) as the T cell growth factor, interleukin-2, became available, the first human oncovirus, HTLV-I, was isolated and proved to be the cause of adult T cell leukemia; 3) HIV was isolated and classified as a lentivirus and as the cause of AIDS. A few years later the antioncogenes were discovered. Both oncogenes and anti-oncogenes were found to collaborate in the cell cycle, maintaining an equilibrium between proliferation and apoptosis. Today the viral theory has been replaced by the gene theory of cancer which postulates that neoplastic transformation is the result of a cascade of events which include uncorrected DNA errors, blocking of apoptosis, activation of oncogenes and deletion of antioncogenes. At the present time, the intriguing question for retrovirologists is the role played by endogenous retroviruses which in man occupy up to 0.1 of the cellular genome.