ヒトT細胞白血病ウイルス1型の生き残り戦略と病原性

Strategy and pathogenesis of human T-cell leukemia virus type 1

はじめに

　ヒトT細胞白血病ウイルス1型（human T-cell leukemia virus type 1：HTLV-1）ははじめてヒトで発見されたレトロウイルスであり，成人T細胞白血病・リンパ腫（adult T-cell leukemia-lymphoma：ATL）の原因ウイルスであることが同定された．1970年代半ばに京都大学の高月らは臨床，疫学的特徴からATLを独立した疾患として報告した^1）．高月らは京都を中心とした患者で検討されたにもかかわらず，患者の出生地が九州地方に集積していることに気づき，その原因として病原体の関与を予測していた．1980年に米国国立衛生研究所のGallo博士らの研究グループはT細胞腫瘍患者からヒトT細胞白血病ウイルス（human T-cell leukemia virus：HTLV）を分離したと報告した^2）．HTLV-1はその後，日沼らによりATLの原因ウイルスであることが明らかとなった^3）．HTLV-1の発見はエイズウイルスの原因であるヒト免疫不全ウイルスの発見へとつながった．しかし，HTLV-1の生き残り戦略と病原性発現機構に関しては不明な点が残されていた．

Abstract

　Adult T-cell leukemia-lymphoma（ATL）has been reported as the distinct disease entity in 1977. In 1980, human T-cell leukemia virus type 1（HTLV-1）was discovered as the first human retrovirus. Thereafter, HTLV-1 was identified as the causative agent of ATL. HTLV-1 encodes regulatory and accessory genes in pX region that is localized between env and 3′ long terminal repeat（LTR）. It has been thought that Tax is responsible for leukemogenesis by HTLV-1. However, I found that Tax expression is inactivated in approximately half of ATL cases. On the other hand, pX region and 3′LTR are conserved in all ATL cases. I revealed that HTLV-1 bZIP factor（HBZ）gene, which is encoded in the minus strand of the provirus, is critical for leukemogenesis. Indeed, HBZ transgenic mice developed T-cell lymphomas and inflammatory diseases. HBZ induces expression of Foxp3, CCR4, and TIGIT in HTLV-1 infected cells, suggesting that HBZ determines immunophenotypes of infected cells and ATL cells. HBZ functions as both encoded protein and RNA. We also found that Tax is transiently expressed in some ATL cell lines. Since Tax is the highly immunogenic protein, infected cells minimize Tax expression. Thus, HTLV-1 has several strategies to survive in vivo and facilitate to transmit to new hosts, which are closely associated with pathogenesis of HTLV-1. Further studies on mechanisms of HTLV-1 pathogenesis will lead to development of new therapeutic strategy on these intractable viral diseases.