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* Center for Chronic Viral Diseases,
Division of Blood Transfusion Medicine, and
Department of Neurology and Geriatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan; and
Center for Information Biology, National Institutes of Genetics, Shizuoka, Japan
Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurological disease. Patients with HAM/TSP show high proviral load despite increased HTLV-I Tax-specific CTL. It is still unknown whether the CTL efficiently eliminate the virus in vivo and/or whether a naturally occurring variant virus becomes predominant by escaping from the CTL. To address these issues, we sequenced a large number of HTLV-I tax genes from HLA-A*02 HAM/TSP patients and estimated synonymous and nonsynonymous changes of the genes to detect positive selection pressure on the virus. We found the pressures in three of six CTL epitopes in HTLV-I Tax, where amino acid substitutions preferentially occurred. Although some of variant viruses were not recognized by the CTL, no variant viruses accumulated within 3–8 years, indicating genetic stability of HTLV-I tax gene. These results suggest that CTL eliminate the infected cells in vivo and naturally occurring variant viruses do not predominate. As Tax is a regulatory protein which controls viral replication, the amino acid substitutions in Tax may reduce viral fitness for replication. Viral fitness and host immune response may contribute to the viral evolution within the infected individuals. Furthermore, the genetic stability in the epitopes despite the antiviral pressures suggests that the three epitopes can be the candidate targets for HTLV-I vaccine development.
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1 This work was supported by a Grant-in-Aid for Research on Brain Science of the Ministry of Health, Labor and Welfare of Japan, and a Grant-in-Aid for Scientific Research of the Ministry of Education, Culture, Sports, Science and Technology of Japan.
2 Address correspondence and reprint requests to Dr. Ryuji Kubota, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan. E-mail address: kubotar{at}m2.kufm.kagoshima-u.ac.jp
3 Abbreviations used in this paper: HTLV-I, human T lymphotropic virus type I; HAM/TSP, HTLV-I-associated myelopathy/tropical spastic paraparesis; Cn, count of nonsynonymous substitutions; Cs, count of synonymous substitutions; sN, nonsynonymous site; sS, synonymous site.
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