Electron microscope image of mouse leukaemia virus-like particles containing a faulty p12 protein.

Kate Bishop : The function of the HIV capsid protein

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The HIV capsid protein (CA) is important for various early, post-entry replication steps and may represent a novel antiviral target. We are studying the function of CA and the interactions it makes with cellular proteins during infection.

The relationship between uncoating (breakdown of the viral core), reverse transcription, trafficking the core to the nucleus and nuclear entry of HIV remain unclear. However, recent evidence suggests that the capsid protein (CA) is central to all early, post-entry replication steps, including nuclear events. The discovery that p12 is essential for MLV integration and interacts with CA supports this notion (see p12 project). The mechanism of uncoating, when and where in the cell it occurs, and which, if any, host proteins contribute to the process are controversial. However, most now agree that perturbing uncoating is detrimental to infectivity and that uncoating is a regulated process. Indeed, uncoating is considered a potential therapeutic target.

Using viral mutants and chemical inhibitors to alter reverse transcription we measured the kinetics of uncoating and determined that HIV-1 uncoating is triggered by a specific step of reverse transcription. This suggests possible mechanisms that drive the uncoating processthat we are continuing to investigate. We are also capitalising on expertise in cryo-electron microscopy at The Crick to develop a novel system to visualise uncoating intermediates that have proved elusive to this point. Knowing the amount and arrangement of CA in the PIC will help elucidate the function of CA during integration. To further these studies we have also characterised a panel of HIV-1 mutants with altered CA shell stabilities. Using these, together with a new fluorescent microscopy technique we are exploring the localisation of CA and the interactions between CA and cellular factors.