Exploiting hepatitis C virus activation of NFκB to deliver HCV-responsive expression of interferons α and γ
Exploiting hepatitis C virus activation of NFκB to deliver HCV-responsive expression of interferons α and γ
复制标题
利用丙型肝炎病毒对 NFκB 的激活来传递干扰素 α 和 γ 的 HCV 响应性表达
作者：
A. Matskevich;D. Strayer
Chronic infection with hepatitis C virus (HCV) may lead to liver failure and hepatocellular carcinoma. Current treatment for HCV includes high systemic doses of interferonα (IFNα), which is effective in less than half of patients and may have severe side effects. We designed conditional IFNα and IFNγ expression constructs to be triggered by HCV-induced activation of NFκB, and delivered these using highly efficient recombinant Tag-deleted SV40-derived vectors. NFκB activates the HIV-1NL4-3 long terminal repeat (HIVLTR) as a promoter, which accounts for the conditional transgene expression. Human hepatocyte lines and primary rat hepatocytes (PRH) were transduced with SV[HIVLTR](IFN) vectors, and transfected with HCV cDNA. Production of human and murine IFNα and IFNγ in cytosol and culture supernatants was measured. HCV activated the HIVLTR to produce and secrete IFNs, and did so largely through the NFκB binding sites of the HIVLTR. Levels of IFNs secreted, and the magnitude of induction in response to HCV, were greater in hepatocyte lines than in primary cultured hepatocytes. However, even in the latter, supernatant IFNα concentrations achieved by this approach were similar to therapeutic serum concentrations sought in systemic IFNα-treated patients. In coculture studies, secreted IFNα activated its cognate response elements in untransduced cells, suggesting that its potential inhibitory effects on HCV may not be limited to transduced cells. Although HCV replication in culture is difficult to assess, HCV-induced IFNα production demonstrably reduced HCV transcription. Conditional expression of IFNs within the liver may represent an attractive approach to therapy of severe chronic HCV infection that could avoid the side effects of systemic treatment regimens.
登录
查看更多内容
影响因子：
5.3
作者：
M. Zamanian-Daryoush;T. Mogensen;J. DiDonato;B. Williams
通讯作者：
M. Zamanian-Daryoush;T. Mogensen;J. DiDonato;B. Williams
SV40 将反式激活的干扰素-α2 递送至 T 细胞，抑制 HIV-1 复制周期的早期阶段。
DOI：
10.1089/152581602760404621
发表时间：
2002
期刊：
Journal of hematotherapy & stem cell research.
影响因子：
--
作者：
Cordelier,Pierre;Calarota,SandraA;Strayer,DavidS
通讯作者：
Strayer,DavidS
生成用于基因转移的重组 SV40 载体。
DOI：
10.1385/1-59259-117-5:103
发表时间：
2001
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Strayer,DS;Lamothe,M;Wei,D;Milano,J;Kondo,R
通讯作者：
Kondo,R
影响因子：
158.5
作者：
McHutchison, JG;Gordon, SC;Albrecht, JK
通讯作者：
Albrecht, JK
SV40 衍生载体对于基因治疗有何作用？
影响因子：
--
作者：
Strayer,DavidS;Zern,MarkA;Chowdhury,JRoy
通讯作者：
Chowdhury,JRoy