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Novel oncogenes and tumor suppressor genes I Mammary carcinomaNeurodegenerative diseases I AIDS

Detection and characterization of novel oncogenes and tumor suppressor genes in leukemia and mammary cancers
Murine leukemia viruses (MuLV) frequently induce leukemia and lymphoma in inoculated mice. Their proviruses integrate in the vicinity of some genes involved in growth regulation and act as insertion mutagens. We are using this approach to identify novel oncogenes involved in T- or B-cell lymphomas induced by various MuLVs. We have succeeded in identifying novel oncogenes which are under characterization. In addition, we are using the differential display technique, coupled with the use of revertant of oncogene transformed cells to identify downstream effectors of transformation.


Mammary carcinoma in transgenic mice
We used the mouse mammary tumor virus (MMTV) long terminal repeat (LTR) to express the oncogene Ha-ras or c-erbB2/neu in transgenic mice. These transgenes, expressed in the mammary glands of our mice, lead to the development of mammary carcinoma at high frequency and stochastically. An interesting feature of the tumors arising in transgenic mice harboring the neu oncogene was their frequent metastasis and their histology type, comedocarcinoma, resembling that found in women's breast tumors. This type of tumors has never been described in mice before. These mice provide an adequate model to understand human breast cancers frequently associated with c-erbB2/neu amplification. These mice are being used to identify novel oncogenes or tumor suppressor genes collaborating with c-erbB2/neu for oncogenesis, as well as to study genes of resistance to the disease.


Studies of the pathogenesis of retrovirus-induced neurodegenerative diseases in mice
Cas-Br-E is a retrovirus inducing a neurodegenerative motor neuron disease in mice, namely a spongiform myeloencephalopathy. We have mapped the viral determinant of pathogenicity within the env (gp70) gene. Recently, we confirmed the important role of gp70 in the disease process by expressing only the env gene of the Cas-Br-E genome in the central nervous system (CNS) of transgenic mice. These mice developed CNS disease. Because gp70 is known to bind to a cell receptor to initiate virus infection, we have postulated that this paralysis is a receptor-mediated disease. Interestingly, the main target cells of this virus in the CNS have been identified as the microglial cells and neurons are not infected. Since neurons degenerate in this disease, they appear to do it by an indirect mechanism, without being themselves infected. Understanding the pathogenesis of this virus-induced disease remains our goal. This disease may represent a good animal model for some known neurodegenerative diseases such as the Creutzfeld-Jakob disease (which shows a similar pathology), the amyotrophic lateral sclerosis (ALS) (which shows a similar distribution of lesions and loss of motor neurons), or other human retrovirus-induced encephalitis induced by HTLV-I or HIV-1.

HIV-1 appears to cause frequent and severe CNS diseases and peripheral neuropathy. Our laboratory is interested in understanding the pathogenesis of the HIV-1-associated diseases and in developing animal models of it. We recently expressed the HIV-1 genome in neurons or in oligodendrocytes of transgenic mice.

These mice developed CNS diseases very similar to those found in AIDS patients. These models are likely to help our understanding of the human diseases and to help in developing therapies.


Acquired immunodeficiency syndrome (AIDS)
Human AIDS is caused by HIV-1. There is no animal model of AIDS with HIV-1 and the best model remains infection of primates with SIV (simian immunodeficiency virus). Our laboratory is interested in developing models of HIV-1 induced AIDS in mice. To do so, we used the promoter of the human CD4 gene to express the HIV-1 genes in transgenic mice. Since CD4 is the receptor for HIV-1, the use of this receptor allowed expression of HIV-1 in the same cells as those normally infected in HIV-1 positive individuals. These CD4C/HIV transgenic mice develop a very severe disease with several phenotypes : thymic atrophy, preferential loss of CD4+ T cells, increase of CD8+ T cells, downregulation of cell surface CD4, interstitial pneumonitis, interstitial nephritis, cardiomyopathy, wasting, failure to thrive, weight loss, diarrhea, early death. All these phenotypes are very similar to those seen in AIDS patients. Recently, we showed that HIV-1 nef gene is mainly responsible for the appearance of these phenotypes and that paradoxically the T cells are constitutively activated and are hyperresponsive to stimulation through the T-cell receptor. The understanding of the pathogenesis of these different phenotypes remain an important goal of our laboratory.

In the above-described transgenic model of AIDS, HIV-1 does not replicate and only post-integration events are studied. We are interested in developing a mice which would be infectable with HIV-1. The main receptor for HIV-1 has been identified as the CD4 molecule. The human CD4 receptor appears to require the association with other co-receptors to allow infection. In order to develop a small animal model of HIV-1 infection, we have constructed a transgenic mouse expressing the human CD4 and co-receptor genes faithfully and at high levels in the appropriate cell types. These mice should be useful for infection with HIV-1 in vivo.

We are also studying a retrovirus-induced disease in mouse which exhibits severe T cell anergy and which has been designated as murine AIDS or MAIDS. We have identified the pathogenic virus as a defective retrovirus. Interestingly, the disease can be induced with helper-free stocks of defective virus, in the absence of virus replication. The genome of this defective virus codes for a single gag precursor protein (Pr60gag). Intact myristylated Pr60gag is required for disease induction as have indicated studies with various mutants. We have now evidence that Pr60gag behaves as a signaling molecule. The target cells of the virus appear to be peripheral B cells, located in germinal centers. After infection, these cells start to proliferate. It seems that the immune defects of T cells are secondary to this B cell expansion. We are postulating that these infected B cells produce a new factor responsible for anergizing T cells. We believe that this murine disease may represent a good model to study and understand the pathogenesis of other immunodeficiencies, including human AIDS.

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