H. saimiri tyrosine-kinase interacting protein inhibits Tat function: a prototypic strategy for restricting HIV-1-induced cytopathic effects in immune cells.
H. saimiri tyrosine-kinase interacting protein inhibits Tat function: a prototypic strategy for restricting HIV-1-induced cytopathic effects in immune cells.
复制标题
H. saimiri 酪氨酸激酶相互作用蛋白抑制 Tat 功能：限制 HIV-1 诱导的免疫细胞细胞病变效应的原型策略。
DOI：
10.1016/j.virol.2006.04.016
复制
发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Henderson,EarlE
中科院分区：
文献类型：
--
作者：
Raymond,AndreaD;Hasham,Muneer;Tsygankov,AlexanderY;Henderson,EarlE
人类疱疹病毒Simiri(HVS)转化的人T细胞对人类免疫缺陷病毒1型(HIV-1)的X4和R5毒株具有容许性，证据表明与T细胞转化相关的人类疱疹病毒编码蛋白增强了HIV-1的复制。分析转化相关的双顺反子HVS开放阅读框架(ORF)对HIV-1复制的贡献，发现第二个ORF saimiri转换相关蛋白C型(StpC)的表达赋予了T细胞允许的表型。相反，在没有StpC的情况下，第一个HVS ORF酪氨酸激酶相互作用蛋白(TIP)的表达增强了对T细胞系和外周血单核细胞中HIV-1复制的限制。了解TIP增强限制HIV-1复制的机制可能会发现可以作为治疗靶点的独特途径。在这里，我们报告TIP限制单核细胞来源的细胞系中HIV-1的复制，并限制携带前病毒的T细胞系中HIV-1复制的重新激活。在这份报告中，我们开始解开TIP介导的限制的分子基础。TIP介导淋巴细胞特异性激酶(LCK)依赖和非依赖的HIV-1复制效应。我们还提供了证据表明，TIP介导的限制在一定程度上是由于抑制了HIV-1长端重复序列(LTR)的TAT反式激活。TIP在T细胞中的表达增加了STAT1和STAT3的激活，以及蛋白激酶RNA化(PKR/P68)和干扰素-γ的产生。综上所述，这些结果提供了证据，证明TIP通过抑制HIV-1转录同时诱导细胞间抗病毒状态来限制HIV-1的复制和重新激活。我们认为，驱动TiP表达的基因工程载体可以为限制HIV-1在不同细胞系中的复制和重新激活提供一种原型策略。
Herpesvirus saimiri (HVS)-transformed human T cells become permissive for X4 and R5 strains of human immunodeficiency virus type 1 (HIV-1), evidence that HVS-encoded proteins associated with T cell transformation enhance HIV-1 replication. Analyzing the contribution of transformation-associated bicistronic HVS open reading frames (ORF) to HIV-1 replication revealed expression of the second ORF saimiri transformation-associated protein type C (StpC) conferred the permissive phenotype to T cells. In contrast, expression of the first HVS ORF tyrosine-kinase interacting protein (Tip) in the absence of StpC enhanced restriction of HIV-1 replication in T cell lines and peripheral blood mononuclear cells. Understanding the mechanism whereby Tip enhanced restriction of HIV-1 replication may uncover unique pathways that could be targeted therapeutically. Here we report that Tip restricts HIV-1 replication in a monocyte-derived cell line and restricts reactivation of replication of HIV-1 in a T cell line harboring provirus. In this report, we begin to unravel the molecular underpinnings of Tip-mediated restriction. Tip mediates both lymphocyte-cell-specific kinase (Lck)-dependent and -independent effects on HIV-1 replication. We also provide evidence that Tip-mediated restriction is in part due to inhibition of Tat transactivation of the HIV-1 long terminal repeat (LTR). Expression of Tip in T cells increased activation of Stat1 and Stat3, as well as activation of protein kinase RNA-dependent (PKR/p68) and interferon-γ production. Taken together, these results provide evidence that Tip restricts HIV-1 replication and reactivation by inhibiting HIV-1 transcription while inducing an intercellular antiviral state. We propose that genetically engineered vectors driving Tip expression could provide a prototypic strategy for restricting HIV-1 replication and reactivation in diverse cell lineages.