Role of nucleic acid structure in HIV-1 replication

由人类免疫缺陷病毒1型(HLV-1)引起的获得性免疫缺陷综合征(AIDS)是21世纪初化疗面临的最大挑战之一。在缺乏有效疫苗的情况下，HLV-1逆转录酶和蛋白酶抑制剂的组合为控制艾滋病毒感染提供了强有力的支持。最近，HLV-1整合酶抑制剂也被添加到该药物方案中。然而，开发针对HIV-1的有效疗法的一个主要挑战是出现含有病毒酶突变的多重耐药病毒株。因此，获得这些关键病毒酶的详细机制信息对于继续开发更好的药物是至关重要的。 在HLV-1复制过程中，HLV-1逆转录酶将RNA基因组逆转录成具有整合能力的双链DNA。这种病毒DNA随后通过HLV-1整合酶整合到宿主基因组中。我的长期目标是破译逆转录病毒复制过程中基本的病毒和细胞酶与其核酸底物之间相互作用的分子细节。 这是基于我的初步和已发表的数据，其中核酸结构的变化 HLV-1逆转录酶对其识别的影响。该提议的中心假设是，核酸的结构在逆转录病毒复制过程中发挥着重要作用。我的假设的基本原理是基于逆转录病毒酶适应构象不同的核酸底物的方式。利用我的核苷类似物方法和拟议的病毒学培训，我将以特定的目标验证我的假设：1)核酸结构/几何结构如何影响HLV-1整合；2)APOBEC3G如何识别单链病毒DNA。从我的研究中获得的新的和重要的生化数据将有助于我们理解HLV-1的复制机制，即 这对于设计更好、更有效的抗艾滋病毒药物至关重要。

Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus type 1 (HlV-1) is one of the most important challenges for chemotherapy of the early 21 st century. In the absence of an effective vaccine, a combination of inhibitors of HlV-1 reverse transcriptase and protease provide strong support for control of HIV infection. Recently, HlV-1 integrase inhibitors have also been added to this drug regimen. However, a major challenge in developing an effective therapy against HIV-1 is the emergence of multidrug-resistant virus strains, containing mutations in viral enzymes. Therefore, it is essential to obtain detailed mechanistic information on these key viral enzymes for the continued development of better drugs. During HlV-1 replication, the RNA genome is reverse transcribed into an integration competent double stranded DNA by HlV-1 reverse transcriptase. This viral DNA is subsequently integrated into the host genome by the HlV-1 integrase. My long term goal is to decipher the molecular details of interactions between essential viral and cellular enzymes with their nucleic acid substrates during retroviral replication. This is based on my preliminary and published data, where alterations in nucleic acid structure have influenced their recognition by HlV-1 reverse transchptase. The central hypothesis of the proposal is that structures of nucleic acids play an important role during retroviral replication. The rationale of my hypothesis is based on the manner in which retroviral enzymes accommodate conformationally-distinct nucleic acid substrates. Exploiting my nucleoside analog methodology and proposed virology training, I will validate my hypothesis with specific aims: 1) How does the nucleic acid structure/geometry influence HlV-1 integration and 2) How APOBEC3G recognizes the single stranded viral DNA. New and important biochemical data obtained from my studies will facilitate our understanding on the mechanism of HlV-1 replication, which is essential to design better and effective drugs against HIV.