Host Defense Regulation by HTLV-1

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Adult T cell leukemia-lymphoma (ATLL) is an aggressive and generally fatal tumor associated with Human T cell Leukemia Virus Type 1 (HTLV-1). ATLL, a CD4 helper T cell malignancy, presents clinically as either a chronic disease that may progress, as an acute leukemia or high grade lymphoma. ATLL pafients fare very pooriy with conventional chemotherapeutic regimens, however therapy with azidothymidine (AZT) and interferon alpha (IFN-a) has produced long-term clinical remissions in a subset of patients. Little is known of the molecular pathogenesis of ATLL. Suitable animal models for the disease have been lacking and HTLV-1 transformed lines differ substanfially from the primary tumors. Most research has centered on the role of the viral oncoprotein tax although it is not expressed in primary tumors. Research on HTLV-1 and oncogenesis is further complicated by the prolonged latency between the time of infection and the development of overt disease. In order to study this tumor and identify subgroups of ATLL that may be amenable to AZT/IFNo (or other) therapies one must have access to a large number of primary isolates. HTLV-1 related diseases are a significant health care problem in certain US communities, in afro-Caribbean and afro-Latin communities. Miami is an endemic area for the HTLV-1 virus as is Salvador, the capital of the northeastern Brazilian state, Bahia. Through a collaboration between the University of Miami and the Federal University of Bahia we have identified several important molecular features related to the pathogenesis, therapy and prognosis of ATLL. We have defined two forms of the disease, one that is responsive to AZT/IFNa and another that is resistant. Response or lack thereof correlates with nuclear NF-kB subunit composifion and IFN signaling properties. We have also found that patients in remission while on long-term antiviral therapy have persistent T cell clones detectable in peripheral blood mononuclear cells (PBMC's). We propose to study primary ATLL in pafients at our institution and at our collaborators site. We will follow patients enrolled on an anfiviral clinical trial to determine the molecular characteristics of sensitive and resistant disease. This translational study which is thematically linked to this overall proposal (IFN and innate immune signaling) has great potential to begin to elucidate the molecular processes of ATLL progression as well as define the subset of pafients most likely to benefit from therapy. RELEVANCE (See instructions): HTLV-1 related ATLL is a deadly disease that predominanfiy affects Afro-Caribbean and African Americans in our community (South Florida). The disease is also quite common in Afro-Lafin populafions. The study of ATLL presents some technical difficulties and investigation of the actual tumor requires access to primary pafient material. We present in our proposal a translafional study of the biology of AZT/IFNa sensifive and resistant ATLL coupled with a clinical trial. We have substanfial experience with this disease and our project is closely integrated with the two other proposals in this application.