Despite advances in the understanding of the in vitro molecular mechanisms of human T cell lymphotropic virus type 1 (HTLV-1), the development of appropriate and coordinated animal model systems to study the virus has not kept pace with this knowledge. The recent availability of molecular clones of the virus provides a unique opportunity to understand the pathogenesis of this important human pathogen. HTLV-1 infection exists worldwide, but is a particular problem in endemic regions of the United States. HTLV-1 infection causes adult T-cell leukemia/lymphoma (ATL) and is associated with a variety of immune- mediated disorders including HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 is a complex retrovirus containing typical gag, pol, and env genes, as well as unique regulatory and accessory genes. Regulatory and accessory genes of HTLV-1 are encoded in four open reading frames (ORF I-IV) of the pX region of the virus. Tax, a 40 kD protein encoded from ORF IV plays a critical role in the regulation of both viral and cellular genes involved in lymphocyte proliferation. Rex, a 27 kD phosphoprotein, derived from ORF III, regulates the expression of incompletely spliced viral transcripts. It is not clear, however, what role ORFs I and II play in the pathogenesis of the virus infection. Our long term goal is to refine or develop animal models to study genetic determinants of HTLV-1 that allow the establishment of infection in vivo and lead to the transformation of CD4+ T lymphocytes. Our research group has established infectious molecular clones of HTLV-capable of CD4+ lymphocyte transformation as intact clones or with selective ablations of regulatory genes. In addition, we have developed Tax-independent HTLV-1 clones to differentiate the role of Tax from other regulatory elements of the virus. Using similar methods we were the first to identify a functional role of p12/I in establishment of infection in a rabbit model. Our collaborators, have adapted the SCID mouse model to address issues regarding HTLV-1 leukemogenesis and using transgenic mice have targeted Tax to the nature T lymphoid compartment providing new insight in the development of lymphoid tumors. We are now poised to develop and refine innovative animal model systems to address fundamental issues regarding the molecular mechanisms of the pathogenesis of HTLV-1 infection.
Specific aims that will be addressed in our infectivity of HTLV-1 and 2) Develop and evaluate SCID/beige and transgenic mouse model systems to test the in vitro and in vivo effects of selective mutations in tax and ORF I and II of htlv-1. Thus, we will compare the effects of each mutation in virus replication (rabbit model), tumor outgrowth in context to the full-length virus (SCID/bg model), and as isolated genes (transgenic model.) This type of comprehensive evaluation using common molecular clones has not been reported. Collectively, our research groups provide a coordinated approach to develop state-of-the-art animal models to further knowledge of the events of HTLV-1 pathogenesis.
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