Genomic RNA control of HIV viral assembly and export

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HIV remains a major cause of illness and death worldwide despite major advances in the diversity and efficaciousness of available drugs to treat the virus. HIV is an RNA virus which encapsidates two copies of its RNA genome into each virus particle. This is a process which the virus achieves by a very specific interaction between domains of the major structural viral protein Gag and a region of the viral full length genomic RNA which has folded up to form a uniquely recognisable three dimensional shape. The folding up of the RNA is dependent on the nucleotide sequence of the virus RNA so this particular structure can only be formed by the HIV genome. Many of the details about how the virus assembles itself and captures its genetic material as it leaves the cell are still incompletely understood. Because of this it is a part of the lifecycle which is a currently unexploited therapeutic target. We know many of the cellular and viral proteins involved but how they interact with the RNA genome is still not fully elucidated. We have now found evidence that the virus uses the presence of its genetic material, RNA, as a quality control measure to regulate the efficiency of virus export. Only viruses which contain the RNA genome undergo the correct maturation steps and bud with optimal efficiency from the infected cell. This is important for the virus since a particle that budded out without capturing any genetic material would not be infectious. Our data show that the presence of the RNA controls how the virus assembles and how the virus matures into an infectious particle. The presence of the RNA also seems to ensure correct interactions between viral and cellular proteins which are used to facilitate budding. Much is known about the protein factors involved in virus budding but until now the way the RNA component controls the process has largely been ignored. Our published and preliminary data indicates that there are important interactions between the viral RNA and viral and cellular proteins that can be exploited as new ways to inhibit virus replication. We will analyse this process to establish and characterise specific interactions of the viral RNA with cellular proteins, some of which we have already identified. We will use the most modern techniques for identifying RNA/protein interactions, including some that we have developed ourselves. We will also use super resolution microscopy and crystallography to visualise the core components of a budding complex of the virus and how the different components interact. By understanding these processes fully we will be able to identify new potential targets for drug intervention. We have already exploited part of this process (involving purely viral components) as a drug target and this is the subject of an ongoing collaboration with Glaxo SmithKline. More detailed knowledge of processes involving cellular proteins will provide new targets which the virus will have difficulty escaping from and which will add usefully to the armamentarium of drugs available to treat this infection.