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

点击翻译按钮获取中文摘要

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.