Raymond Andrea D, Hasham Muneer, Tsygankov Alexander Y, Henderson Earl E
Department of Microbiology and Immunology, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140, USA.
Virology. 2006 Sep 1;352(2):253-67. doi: 10.1016/j.virol.2006.04.016. Epub 2006 Jun 15.
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-gamma 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.
猴疱疹病毒（HVS）转化的人T细胞对1型人类免疫缺陷病毒（HIV-1）的X4和R5毒株变得易感，这表明与T细胞转化相关的HVS编码蛋白可增强HIV-1复制。分析与转化相关的双顺反子HVS开放阅读框（ORF）对HIV-1复制的贡献发现，第二个ORF即猴病毒转化相关蛋白C型（StpC）的表达赋予T细胞易感表型。相反，在缺乏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HIV-1复制限制的机制可能会揭示出可用于治疗靶向的独特途径。在此我们报告，Tip在单核细胞衍生细胞系中限制HIV-1复制，并在含有前病毒的T细胞系中限制HIV-1复制的重新激活。在本报告中，我们开始揭示Tip介导的限制的分子基础。Tip对HIV-1复制介导淋巴细胞特异性激酶（Lck）依赖性和非依赖性作用。我们还提供证据表明，Tip介导的限制部分是由于抑制HIV-1长末端重复序列（LTR）的Tat反式激活作用。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依赖性（PKR/p68）的激活和干扰素-γ的产生。综上所述，这些结果提供了证据表明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复制和重新激活。我们提出，驱动Tip表达的基因工程载体可为限制不同细胞谱系中HIV-1复制和重新激活提供一种原型策略。
