Polygenic Control of Human T Lymphotropic Virus Type I (HTLV-I) Provirus Load and the Risk of HTLV-I–Associated Myelopathy/Tropical Spastic Paraparesis

Human T lymphotropic virus type I (HTLV-I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) is one outcome of infection with HTLV-I. A population association study of 229 patients with HAM/TSP and 202 healthy carriers of HTLV-I in southern Japan showed that this outcome of HTLV-I infection and the HTLV-I provirus load are under polygenic control. Of 58 polymorphic sites studied in 39 non-HLA candidate gene loci, 3 new host genetic factors that influenced the risk of HAM/TSP or the provirus load of HTLV-I were identified. The promoter TNF 863A allele predisposed to HAM/TSP, whereas SDF-1 +801A 3 � UTR, and IL-15 191C alleles conferred protection. Knowledge of HTLV-I–infected individuals’ ages, sex, provirus load, HTLV-I subgroup, and genotypes at the loci HLA-A, HLA-C, SDF-1, and TNF-a allowed for the correct identification of 88% of cases of HAM/TSP in this Japanese cohort. Human T lymphotropic virus type I (HTLV-I), a member of the Oncovirus family, is the etiological agent of 2 diverse diseases: the neurological disorder HTLV-I–associated myelopathy/tropical spastic paraparesis (HAM/TSP) [1, 2] and adult T cell leukemia/lymphoma [3]. The outcome of HTLV-I infection depends on both host genetic and viral factors. At best, an individual may exhibit a life-long asymptomatic infection; at worst, either an inflammatory disease or rapidly fatal leukemia may ensue. Here, we provide evidence for the involvement of host genetic and viral subgroup factors [4] in HAM/TSP in a region of southern Japan (Kagoshima) where HTLV-I is endemic, using an association study and appropriate statistical analyses to predict disease outcome and provirus load. Although different virus strains (denoted HTLV-I subgroups) can influence the risk of developing HAM/TSP [4], the impact of HTLV-I viral sequence variation in determining the risk of developing HAM/TSP in Kagoshima is limited, and no se