An 85-aa segment of the GB virus type CNS5A phosphoprotein inhibits HIV-1 replication in CD4+ Jurkat T cells
An 85-aa segment of the GB virus type CNS5A phosphoprotein inhibits HIV-1 replication in CD4+ Jurkat T cells
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DOI：
10.1073/pnas.0604728103
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发表时间：
2006-10-17
影响因子：
11.1
通讯作者：
Stapleton, Jack T.
中科院分区：
文献类型：
--
作者：
Xiang, Jinhua;McLinden, James H.;Stapleton, Jack T.
GB病毒C型(GBV-C)是一种在T和B淋巴细胞中复制的非致病性病毒，是人类持续感染的常见原因。在HIV-1感染者中，持续感染GBV-C与延长生存时间有关，体外感染GBV-C和HIV的血液单个核细胞或CD4(+)T细胞可显著降低HIV-1的复制。到目前为止，导致抑制艾滋病毒的病毒蛋白(S)尚未确定。据预测，GBV-C非结构磷蛋白(NS5A)对细胞具有趋化作用，包括与干扰素诱导的dsRNA激活的蛋白激酶(PKR)相互作用。我们对GBV-C NS5A进行了研究，以确定它是否参与了抑制HIV复制。经干扰素处理的分离物中的GBV-C NS5A蛋白不抑制PKR，而未被干扰素清除的分离物中的NS5A蛋白在酵母遗传系统中抑制PKR功能。这两种GBV-C NS5A蛋白均在CD4+T细胞系Jurkat中表达，均能有效抑制HIV-1复制，且呈剂量依赖关系，因此其作用不依赖于PKR抑制。NS5A诱导趋化因子SDF-1的释放，并降低HIV辅助受体CXCR4的表面表达，这可能是HIV抑制的原因。NS5A蛋白的缺失图谱发现，152和237个氨基酸之间的85-AA区域抑制了HIV-1的复制。因此，GBV-C NS5A蛋白改变了HIV-1复制所必需的细胞环境，并可能为抗HIV治疗提供一种以前未描述的治疗方法。
GB virus type C (GBV-C) is an apparently nonpathogenic virus that replicates in T and B lymphocytes and is a common cause of persistent human infection. Among HIV-1-infected individuals, persistent coinfection with GBV-C is associated with prolonged survival, and infection of blood mononuclear cells or CD4(+) T cells with GBV-C and HIV in vitro results in significantly reduced HIV-1 replication. To date, the viral protein(s) that lead to HIV inhibition have not been identified. The GBV-C nonstructural phosphoprotein (NS5A) is predicted to have pleotropic effects on cells, including interactions with the IFN-induced dsRNA-activated protein kinase (PKR). We studied GBV-C NS5A to determine whether it is involved in inhibition of HIV replication. GBV-C NS5A protein from an isolate that was cleared by IFN therapy did not inhibit PKR, whereas NS5A from an isolate that was not cleared by IFN-inhibited PKR function in a yeast genetic system. Both of these GBV-C NS5A proteins were expressed in a CD4+ T cell line (Jurkat), and both induced a potent, dose-dependent inhibition of HIV-1 replication, thus the effect was independent of PKR inhibition. NS5A induced the release of the chemokine SDF-1 and decreased surface expression of the HIV coreceptor CXCR4, potentially explaining the HIV inhibition. Deletion mapping of the NS5A protein found that an 85-aa region between amino acids 152 and 237 inhibits HIV-1 replication. Thus, GBV-C NS5A protein alters the cellular milieu necessary for HIV-1 replication and may provide a previously undescribed therapeutic approach for anti-HIV therapy.