Human T Cell Leukemia Virus Type I (HTLV-I) Molecular Genotypes and Disease Outcome

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Abstract
The approach taken in our laboratory to determine viral markers associated with human T cell leukemia virus type I (HTLV-I) disease induction was to compare viral genomes and host immune responses from HTLV-I-infected patients from two geographical areas with significant differences in the incidence rate of tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM), Tumaco, Colombia, and Kyushu Island, Japan. These studies showed that TSP/HAM patients have higher antibody levels against viral antigens and a higher proviral load compared to asymptomatic carriers and adult T cell leukemia (ATL) patients. A mutation in the tax gene was found to be associated with TSP/HAM, which in turn correlates with a higher transactivation activity of Tax. In addition, we found that HTLV-I-infected individuals contain infected cells that are clonally expanded. The genomic structure of these expanded clones shows that defective proviruses are present in asymptomatic carriers. A predilection in the defectiveness, however, was found to correlate with the presence (Cosmopolitan molecular genotype) or absence of the tax mutation (Japanese molecular genotype). Our results suggest that defective proviruses retaining structural genes might be a risk factor for TSP/HAM development. Contrary, defective proviruses retaining regulatory genes in the pX region could be a risk factor for ATL development. The molecular mechanism by which these defective proviruses is generated and expressed should give new insight into HTLV-I pathogenesis.

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