Specific aims: Investigators will: 1. Investigate the prevalence of disease-associated HTLV-1 tax gene mutations in Polynesia. 2. Use HTLV-i as a biological marker to clarify the peopling of the Pacific and the likely origins of Polynesians. Human T-cell lymphotropic virus type I (HTLV-I) is the etiologic agent of a fulminating lymphoroproliferative malignancy, known as adult T-cell leukemia/lymphoma, and a chronic, slowly progressive spastic myelopathy, known as tropical spasticparaparesis/HTLV-i-associated myelopathy (TSP/HAM). The pathogenetic basis of these diseases if poorly understood. In some murine retrovirus infections, tissue tropism and tumorigenicity are determined by the U3 region of the long terminal repeat (LTR) and the env gene. For example, amino acid-altering mutations in the env gene of Moloney murine leukemia virus permit preferential virus replication in neurla tissue and resultant hindilimb paralysis in infected mice. Disease-specific LTR and env gene sequences, however, have not been found in strains of HTLV-I isolated from patients with ATLL or TSP/HAM from widely separated geographic regions, including Japan, the Caribben basin, the Americas and Africa (1-3). Moreover, the LTR Nd env gene of HTLV-I strains from asymotomatically infected carriers are genetically indistinguishable from disease-associated strains. Recently, an amino acid-altering (valine to alanine) point mutation in the p40 tax-encoding pX gene, at nucleotide position 7959, was found in HTLV-i isolates from the high-incidence focus of TSP/HAM in Tumaco, Colombia(4). The same p40 tax mutation has been found in some patients with TSP/HAM from Japan and India, as well as in asymptomatic carriers in Tumaco, suggesting thtat this point mutation is associated with an increased risk of disease development.
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