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Tat-RNase H and its use in HIV gene therapy

机译：Tat-RNase H及其在HIV基因治疗中的应用

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A targeted RNase, Tat-RNase H, was designed and tested for its activity in vitro and inhibition of HIV-1 replication in vivo. The Tat-RNase H protein consists of the TAR (trans-activation response) element-binding domain of the HIV-1 Tat (trans-activator of transcription) and the RNase H domain of the HIV-1 reverse transcriptase (RT) (Melekhovets and Joshi, 1996). The Tat protein binds specifically to the TAR element present in all HIV-1 RNA molecules, whereas HIV-1 RNase H specifically degrades RNA within RNA/DNA hybrid in vivo (Skalka and Goff, 1993; Telesnitsky and Goff, 1997) and to a lesser degree within RNA/RNA hybrid in vitro (Ben-Artzi et al, 1992; Gotte et al, 1995). Thus, there are two anticipated modes of action of the Tat-RNase H protein. It could cleave HIV- 1 TAR RNA in RNA/RNA hybrid or in RNA/DNA hybrid. RNA cleavage in RNA/RNA hybrid was previously shown to be specific and to depend on interaction between the Tat domain of Tat-RNase H and the TAR element of HIV-1 RNA (Melekhovets and Joshi, 1996). We demonstrate here that the Tat-RNase H mediated cleavage of RNA in RNA/DNA hybrid is non-specific as both TAR and mutant TAR RNA/DNA hybrids could be efficiently cleaved. A retroviral vector expressing Tat-RNase H was then constructed to assess whether Tat-RNase H can inhibit HIV-1 replication. However, the Tat-RNase H protein failed to inhibit HIV-1 replication in transduced MT4 cells and in peripheral blood T lymphocytes (PBLs). The possible reasons why Tat-RNase H might have failed to inhibit HIV-1 replication in MT4 cells and PBLs are discussed.
机译：设计并测试了靶向的RNase Tat-RNase H的体外活性以及体内对HIV-1复制的抑制作用。 Tat-RNase H蛋白由HIV-1 Tat（转录的反式激活因子）的TAR（反式激活响应）元件结合结构域和HIV-1逆转录酶（RT）的RNase H区域组成（Melekhovets和乔希（1996）。 Tat蛋白特异性结合所有HIV-1 RNA分子中存在的TAR元素，而HIV-1 RNase H特异性降解体内RNA / DNA杂种中的RNA（Skalka和Goff，1993; Telesnitsky和Goff，1997）和在体外，RNA / RNA杂种的亲和力较小（Ben-Artzi等，1992; Gotte等，1995）。因此，Tat-RNase H蛋白有两种预期的作用方式。它可以在RNA / RNA杂种或RNA / DNA杂种中切割HIV-1 TAR RNA。先前显示RNA / RNA杂种中的RNA切割是特异性的，并且取决于Tat-RNase H的Tat域与HIV-1 RNA的TAR元素之间的相互作用（Melekhovets和Joshi，1996）。我们在这里证明，Tat-RNase H介导的RNA / DNA杂合体的裂解是非特异性的，因为TAR和突变TAR RNA / DNA杂合体都可以被有效地裂解。然后构建表达Tat-RNase H的逆转录病毒载体，以评估Tat-RNase H是否可以抑制HIV-1复制。但是，Tat-RNase H蛋白不能抑制HIV-1在转导的MT4细胞和外周血T淋巴细胞（PBLs）中的复制。讨论了Tat-RNase H未能抑制HIV-1在MT4细胞和PBL中复制的可能原因。

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