The mechanism of Tat-enhanced reverse transcription in HIV-1

在逆转录过程中，正链HIV-1 RNA基因组转化为双链DNA拷贝，可永久插入宿主细胞基因组。包括达特在内的许多HIV-1蛋白质有助于逆转录的效率。有两种相互竞争的假说来解释达特如何增强逆转录。间接机制假说认为，Tat增强逆转录是由于Tat诱导的细胞基因表达的联合作用。直接机制假说是达特在RTN过程中直接起作用，这意味着它是一种病毒体蛋白。我们最近的遗传和生物化学数据提供了强有力的证据表明，一种新形式的达特，我们称之为v达特，在RTN中有直接的作用。本提案将探讨这两个主要假设。鉴于艾滋病毒大流行的严重性和美国最近的许多报告，即大多数患者分离的病毒对至少一种抗逆转录病毒药物具有耐药性，这些研究的结果是鉴定和表征了重要的新的关键分子，可以针对这些分子设计抗逆转录病毒策略。

During reverse transcription, the positive-strand HIV-1 RNA genome is converted into a double-stranded DNA copy which can be permanently insert into the host cell genome. Many HIV-1 proteins including Tat contribute to the efficiency of reverse transcription. There are two competing hypotheses to explain how Tat enhances reverse transcription. The indirect mechanism hypothesis holds that Tat-enhanced reverse transcription is due to the combined effects of the Tat-induced expression of cellular genes. The direct mechanism hypothesis is that Tat functions directly during RTN, implying it is a virion protein. Our recent genetic and biochemical data provide strong evidence that a novel form of Tat, which we call vTat, has a direct role in RTN. This proposal will investigate these two leading hypotheses. Given the enormity of the HIV pandemic and the many recent reports from the United States that most patient isolated virus is resistant to at least one antiretroviral drug, these studies have as an outcome the identification and characterisation of important new key molecules towards which antiretroviral strategies can be designed.