カポジ肉腫関連ヘルペスウイルスの複製機構と創薬研究

抄録

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and Castleman's disease. While liposomal doxorubicin has been used as an effective treatment for KS patients, the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen used for PEL patients was reported to have 1-year survival rates of less than 40%. Moreover, the development of anti-KSHV drugs inhibiting viral replication has been delayed. KSHV establishes a lifelong infection in its host and alternates between a “latent infection” and “lytic infection” state. Latent infection is associated with maintenance of the viral genome and transformation of the infected cells. Lytic infection is the process of producing infectious virus. Elucidating the KSHV life cycle and viral replication machinery is essential for developing novel therapeutic approaches and identifying potential drug targets. To tackle these issues, we have been screening for anti-PEL compounds using PEL-derived cell lines and utilizing recombinant KSHV for functional analysis of KSHV coding genes. In particular, we have focused on the “viral pre-initiation complex” of KSHV and determined its molecular mechanism. The coding proteins conserved among β- and γ-herpesviruses form a complex, which has functional homology with the pre-initiation complex of host cells. The complex is indispensable for the expression of viral proteins composing virus particles. This review summarizes the pathogenesis and therapies of KSHV-associated malignancies. Furthermore, we introduce our recent data on KSHV ORF34, which contributes to viral late gene expression via the formation of the viral pre-initiation complex.