Suppressive effect of PARP-1 inhibitor on JC virus replication in vitro
Suppressive effect of PARP-1 inhibitor on JC virus replication in vitro
复制标题
PARP-1抑制剂对JC病毒体外复制的抑制作用
作者：
Nukuzuma;S.;Kameoka;M.;Sugiura;S.;Nakamichi;K.;Nukuzuma;C.;Takegami;T.
进行性多灶性白质脑病（PML）的发病率由于艾滋病大流行、恶性血液病和免疫抑制治疗而增加。最近，在接受免疫调节药物（如那他珠单抗）治疗的患者中，单克隆抗体相关PML病例数量增加。然而，在临床研究中尚未就PML治疗达成共识。为了检查3-氨基苯甲酰胺（3-AB）（一种代表性PARP-1抑制剂）对JC病毒（JCV）复制的抑制作用，使用神经母细胞瘤细胞系IMR-32和IMR适应的JCV进行了DNA复制试验。还使用JCI细胞检查了3-AB对JCV增殖的抑制，JCI细胞是产生持续高JCV滴度的载体培养物。结果表明，通过DNA复制试验、血凝和真实的实时PCR分析判断，PARP-1抑制剂（如3-氨基苯甲酰胺（3-AB））可显著抑制JCV的体外复制和繁殖。研究还表明，3-AB降低了IMR-32细胞中的PARP-1活性。根据MTT测定的结果，3-AB-处理的细胞的酶活性略低于DMSO处理的细胞。然而，JCV增殖的显著抑制与细胞生长的轻微降低无关。据我们所知，这是首次报道PARP-1抑制剂通过降低PARP-1活性显著抑制神经母细胞瘤细胞系中JCV的复制。因此，PARP-1抑制剂也可能是PML的一种新型治疗药物。J. Med. Virol. 85：132-137，2012.© 2012 Wiley Periodicals，Inc.
The incidence of progressive multifocal leukoencephalopathy (PML) has increased due to the AIDS pandemic, hematological malignancies, and immunosuppressive therapies. Recently, the number of cases of monoclonal antibody‐associated PML has increased in patients treated with immunomodulatory drugs such as natalizumab. However, no common consensus regarding PML therapy has been reached in clinical studies. In order to examine the suppression of JC virus (JCV) replication by 3‐aminobenzamide (3‐AB), a representative PARP‐1 inhibitor, a DNA replication assay was carried out using the neuroblastoma cell line IMR‐32 and IMR‐adapted JCV. The suppression of JCV propagation by 3‐AB was also examined using JCI cells, which are a carrier culture producing continuously high JCV titers. The results indicated that PARP‐1 inhibitors, such as 3‐aminobenzamide (3‐AB), suppress JCV replication and propagation significantly in vitro, as judged by DNA replication assay, hemagglutination, and real‐time PCR analysis. It has been also shown that 3‐AB reduced PARP‐1 activity in IMR‐32 cells. According to the results of the MTT assay, the enzyme activity of 3‐AB‐treated cells was slightly lower than that of DMSO‐treated cells. However, the significant suppression of JCV propagation is not related to the slight decrease in cell growth. To our knowledge, this is the first report that PARP‐1 inhibitor suppresses the replication of JCV significantly in neuroblastoma cell lines via the reduction of PARP‐1 activity. Thus, PARP‐1 inhibitors also may be a novel therapeutic drug for PML. J. Med. Virol. 85:132–137, 2012. © 2012 Wiley Periodicals, Inc.