Unit: Oncogenic Virus Epidemiology and Pathophysiology

Director: GESSAIN Antoine

Our group works on the human oncogenic retroviruses HTLV-1/HTLV-2 and on the human herpesvirus HHV-8 and their simian related counterparts. During the year 2005, we have continued ongoing projects and developed new studies on both the clinical, analytical and molecular epidemiology of these viruses and on the physiopathology of the tumoral (Kaposi's sarcoma, adult T cell leukemia and primary effusion lymphoma) and inflammatory associated diseases (tropical spastic paraparesis and myositis). Furthermore, we have discovered a new human retrovirus : HTLV-3.

The Unit of Epidemiology and Physiopathology of Oncogenic Viruses has developed the following projects.

Epidemiology of the Human Herpesvirus 8 (HHV-8) and of the Human T Cell Leukemia Virus type 1 (HTLV-1) in endemic areas of French Guyana and Cameroon (Central Africa). These long term projects concern the intra-familial modes of transmission of these oncogenic viruses and the search for an host genetic susceptibility for acquiring such viruses. Other epidemiological studies regarding HTLV-1 and its associated diseases (Adult T cell leukemia and Tropical spastic paraparesis/HTLV-1 associated myelopathy) are also in progress in French Guyanese populations, especially in a large cohort of pregnant women.

Molecular epidemiology and genetic variability of HTLV-1/2 and related simian retroviruses (STLV). We have continued our studies on the genetic variability of HTLV and STLV in Central Africa. These data strenghten the hypothesis of interspecies transmission from STLV-1, present in monkeys, to humans in these regions leading to the foci of HTLV-1 in some human populations of central Africa. A large epidemiological study on HTLV-2 infection is ongoing both at a clinical and at a molecular level in various ethnic populations, living in a rain forest area of South Cameroon. We also continue our studies on the signification of HTLV-1/2 indeterminate serologies in the Pacific and in central Africa. In this field, we have discovered a new human retrovirus HTLV-3, closely related to the STLV-3, which are widespread in several monkey species of the African continent.

Genetic variability of HHV-8. We have studied the genetic variabilty of the K1 region of HHV- 8 of 35 novel viral strain from Moroccan patients suffering of Kaposi's sarcoma and of several other HHV-8 strains originating from isolated populations as Amerindians and Polynesians. We have aslo discovered a novel β herpesvirus in a chimpanzee.

Studies on the pathogenesis of HTLV-1 have been performed. This includes viro-molecular studies of the central nervous system in patients suffering of TSP/HAM as well as the development of in vitro and ex vivo studies aiming to better understand the role of the Tax protein in the pathogenesis of the polymyositis and inclusion body myositis associated with HTLV-1. A study of the role of activated HTLV-1 infected lymphocytes in the alteration of the blood brain barrier has also been initiated.

Relationship between localisation of the Tax 1 and Tax 2 and their pathogenicity : HTLV-1 and HTLV-2 retroviruses infect CD4+ and CD8+ T cells respectively. Unexpectedly since a viral transactivator must enter the nucleus in order to drive the transcription from the viral promoter, we have recently shown that HTLV-1 and HTLV-2 Tax proteins do not have the same intracellular localization. Tax1 is mainly nuclear while Tax2 is predominant in the cytoplasm. In addition, there is a nice correlation between the activation of the CREB/ATF and NF-kB pathways and the Tax localization, i.e. Tax2 activates more efficiently the NF-kB pathway, while Tax1 is a better activator of the CREB/ATF pathway. Since the publication of these data, two other laboratories reported the same observations.

We have now demonstrated that the sequence of the first 110 amino acids of Tax is critical for the protein localization, and that the minimal domain that drives Tax localization corresponds to the 90-100 amino-acids. Finally, we have also demonstrated that Tax2 sequence encompasses a Nuclear Export Signal (NES) in the 188-200 amino acid sequence. We are currently investigating both, in vivo and in vitro, whether there is a correlation between the Tax localization and the viral pathogenicity.

In vivo clonality of HHV-8 associated diseases. Studies are focused on the different forms of Kaposi's sarcoma and on the multifocal aspects of such disease as well as on the primary effusion lymphomas. Our studies are aimed to a better understanding of the role of the latent HHV-8 in the causal relationship of HHV-8 and the associated tumors in vivo.

For most of these studies, the collaboration with numerous colleagues of the Network of the Institut Pasteur and Instituts associés (especially Cameroon, Central African Republic and French Guyana) has been crucial. We have also collaborated with several clinicians from the Paris Hospitals.

Keywords: Retroviruses, HTLV, STLV, herpesviruses, epidemiology, genetic variability, pathogenesis

Activity Reports 2005 - Institut Pasteur

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