Assembly Cofactors of HIV-1

概述HIV-1是导致全球艾滋病流行的病毒。虽然大多数艾滋病毒感染者的艾滋病进展可以通过抗逆转录病毒药物来预防，使艾滋病毒感染者过上正常的生活，但没有治愈方法，患者必须终生服用这些药物。此外，艾滋病毒有时会对常用的抗逆转录病毒药物产生耐药性，药物本身可能导致严重的合并症，使病情的管理更加困难。对艾滋病毒复制和感染的基本生物学原理的进一步科学研究将促进新型药物的开发，为临床医生提供更多的选择来管理艾滋病毒。增加我们对病毒生命周期的基本了解也将有助于致力于开发终身治疗HIV感染的工作。在其复制周期中，HIV感染细胞并将其RNA病毒基因组的DNA拷贝插入细胞基因组中。然后，细胞分子机器被增选以产生形成新的感染性病毒颗粒所需的所有病毒蛋白质。然后这些蛋白质和病毒基因组移动到细胞膜上，在那里它们组装成新的病毒颗粒并从细胞表面出芽;这些颗粒继续感染新的细胞，从而维持和传播感染。有几条科学证据表明，HIV-1的组装过程取决于病毒成分和各种细胞辅因子之间的相互作用。然而，目前的知识，这些关键的细胞辅因子的身份是远远不够的。这为我们提供了一个重要的机会，发现新的HIV复制调节剂，其治疗抑制有可能阻止病毒的生长。我们的研究计划将：i）使用最先进的技术来识别HIV组装的新辅因子，ii）定义它们与病毒成分相互作用的分子机制，并确定这些如何促进病毒的组装。由于这些辅助因子对病毒复制很重要，它们的鉴定将为探索新的抗逆转录病毒药物的开发提供循证平台。

Lay summaryHIV-1 is the virus responsible for the worldwide AIDS pandemic. Although progression to AIDS in the majority of HIV-infected patients can be prevented with antiretroviral drugs, allowing people infected with HIV to life a normal life, there is no cure and such drugs must be taken for the rest of the patient's life. Additionally, HIV sometimes develops resistance to commonly used antiretrovirals and the drugs themselves can cause serious co-morbidities, making management of the condition more difficult. Further scientific research into the fundamental biological principles of HIV replication and infection will facilitate the development of new classes of drug, giving clinicians more options to manage HIV. Increasing our basic understanding of the virus lifecycle will also help work that aspires to develop life time cures for HIV infection.In its replication cycle, HIV infects a cell and inserts a DNA copy of its RNA viral genome into the cellular genome. The cellular molecular machinery is then co-opted to produce all the viral proteins that are needed to form new infectious virus particles. These proteins plus the virus genome then move to the cell membrane where they assemble into new virus particles and bud away from the cell surface; these particles proceed to infect new cells thereby sustaining and spreading the infection. There are several lines of scientific evidence indicating that the process of HIV-1 assembly is dependent on interactions between virus components and various cellular cofactors. However, current knowledge of the identities of these critical cellular cofactors is far from complete. This provides us with an important opportunity to discover novel regulators of HIV replication, whose therapeutic inhibition has the potential to block virus growth.Our proposed research will: i) use state-of-the-art technologies to identify novel cofactors of HIV assembly, and ii) define the molecular mechanisms that underlie their interactions with virus components and determine how these promote assembly of the virus. As these cofactors are important for the virus to replicate, their identification will provide the evidence-based platform from which to explore the development of new antiretroviral drugs.