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

由于成人、儿童和青少年艾滋病毒-1感染继续在世界范围内蔓延，开发进一步的抗逆转录病毒治疗方法仍然是最重要的；例如，没有有效的HIV-1疫苗，目前针对病毒逆转录酶和蛋白酶的一线治疗受到依从性、毒性和病毒耐药性问题的影响。因此，寻找其他HIV-1（或人类）蛋白作为抗病毒靶点是至关重要的，但它们的理性选择需要对潜在的生物学原理有基本的了解。许多实验室的工作有助于目前对病毒组装的理解。在受感染的细胞中形成新生感染性颗粒，准备释放和随后的病毒传播的过程。解决HIV-1生命周期关键步骤的一种实验方法是在它们无功能的环境中研究它们，例如，在来自非人类物种的细胞中。事实上，已经明确地确定HIV-1在小鼠细胞中的组装效率明显低下。在这里，我们将利用这种物种特异性缺陷以及互补的遗传和蛋白质组学方法来鉴定对感染性HIV-1颗粒组装重要的新型细胞辅因子。功能的潜在基础将通过当代生化，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分子运动如何影响蛋白质功能的新见解，以及如何阻碍这些过程以实现病毒抑制。最后，确定的辅助因子将应用于培养的小鼠细胞系统，旨在重现HIV-1感染的传播，这是该领域尚未完成的壮举：实现这一点尤其重要，因为它将为建立HIV-1感染的活体小鼠模型铺平道路，这将对HIV/AIDS发病机制，疫苗和治疗方法的研究具有巨大的效用。九广国际的公共关系部主要负责向公众传达我们的工作；a呢？专家名录？，使公众能够识别愿意讨论专业领域的学者。例如，MHM多次接受媒体采访，出现在电视上，并就艾滋病相关节目的内容向英国广播公司提供建议。他还是公共获取期刊《公共科学图书馆·病原体》的编辑，在社区联络会议（例如，Cafe Scientifique）上举办了关于科学研究价值的概述研讨会，并帮助组织由艾滋病毒/艾滋病界的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.