Exploiting species-specific defects in virion assembly to identify cellular co-factors for HIV-1 replication

随着成人、儿童和青少年艾滋病毒-1感染继续在世界各地传播，进一步抗逆转录病毒治疗的开发仍然至关重要；例如，没有有效的艾滋病毒-1疫苗，目前针对病毒逆转录酶和蛋白酶的一线治疗因依从性、毒性和病毒耐药性问题而受到影响。因此，寻求其他HIV-1(或人类)蛋白质作为抗病毒靶标是至关重要的，但它们的合理选择需要对潜在的生物学原理有基本的理解。许多实验室的工作有助于目前对病毒组装的理解？新生的传染性颗粒在受感染的细胞中形成，为释放和随后几轮病毒传播做好准备的过程。解决HIV-1生命周期中关键步骤的一个实验方法是在它们不起作用的情况下进行研究，例如在来自非人类物种的细胞中进行研究。事实上，已经清楚地证实，HIV-1在小鼠细胞中的组装效率明显低下。在这里，我们将利用这一物种特有的缺陷以及补充遗传和蛋白质组学方法来识别对组装具有感染性的HIV-1颗粒至关重要的新的细胞辅助因子。功能的基本基础将通过当代的生化、分子遗传学和成像实验来解决，例如，期望我们将获得关于细胞内RNA分子的运动如何影响蛋白质功能的新见解，以及如何阻止这些过程来实现病毒抑制。最后，已确定的辅助因子将应用于旨在总结艾滋病毒-1感染蔓延的培养小鼠细胞系统，这是该领域尚未完成的一项壮举：实现这一点特别重要，因为它将为建立艾滋病毒-1感染的活鼠模型铺平道路，这将对艾滋病毒/艾滋病的发病机制、疫苗和疗法等研究具有巨大的实用价值。九龙总公司的公共关系部主要负责向公众宣传我们的工作；专家名录？使公众能够找到愿意讨论专业领域的学者。例如，MHM接受了媒体的多次采访，出现在电视上，并就艾滋病相关节目的内容向BBC提供建议。他也是公共获取期刊《公共科学图书馆·病原体》的分部编辑，曾在社区联络会议(如Cafe Science fique)上就科学研究的价值举行概述研讨会，并帮助组织艾滋病毒/艾滋病社区非科学成员参加的会议。

As adult, paediatric and adolescent HIV-1 infections continue to spread worldwide, the development of further anti-retroviral treatments remains of the utmost importance; for instance, there is no effective HIV-1 vaccine, and current front-line therapies targeting the viral reverse transcriptase and protease enzymes are compromised by compliance, toxicity and viral resistance concerns. Pursuing other HIV-1 (or human) proteins as anti-viral targets is therefore critical, but their rational selection requires a fundamental understanding of underlying biological principles. Work from many laboratories has contributed to the current understanding of virus assembly ? the process where nascent infectious particles are formed in infected cells in readiness for release and subsequent rounds of viral spread. One experimental approach for addressing key steps in the HIV-1 life cycle is to study them in contexts where they are non-functional, e.g., in cells derived from non-human species. Indeed, it has been clearly established that HIV-1 assembly is markedly inefficient in mouse cells. Here, we will exploit this species-specific defect together with complementing genetic and proteomic methodologies to identify novel cellular co-factors important for the assembly of infectious HIV-1 particles. The underlying basis for function will be addressed using contemporary biochemical, molecular genetic and imaging experiments, with the expectation, for instance, that we will gain novel insight into how the movement of RNA molecules within cells can impact protein function, and how these processes may be impeded to achieve viral inhibition. Lastly, the co-factors that are identified will be applied to cultured mouse cell systems that aim to recapitulate spreading HIV-1 infection, a feat not yet accomplished in the field: achieving this is particularly important as it would pave the way for establishing a living mouse model for HIV-1 infection, which would have tremendous utility for, inter alia, studies of HIV/AIDS pathogenesis, vaccines and therapeutics. The Public Relations Dept of KCL is primarily responsible for communicating our work to the public; and a ?Directory of Experts? is maintained that enables members of the public to identify academics willing to discuss specialist areas. For instance, MHM has given numerous interviews to the press, has appeared on television and has advised the BBC on the content of AIDS-related programming. He is also a Section Editor of a public access journal, PLoS Pathogens, has given overview seminars on the value of scientific research at Community Liaison Meetings (e.g., Cafe Scientifique), and helps organise Conferences attended by non-scientific members of the HIV/AIDS community.