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Characterisation and Manipulation of Primate Lentiviral Interactions with Innate Immunity

Final Report Summary - HIVINNATE (Characterisation and Manipulation of Primate Lentiviral Interactions with Innate Immunity)

All cells present a very hostile environment to viral infection. Over millions of years mammals have evolved a series of intra-cellular defensive antiviral pathways and mechanisms that protect effectively against the vast majority of viruses. Nonetheless, human viruses successfully infect human cells. Our research programme has sought to understand how HIV evades these intracellular defences and then to use this information to design novel antiviral drugs that inhibit infection by enhancing our natural cellular defences. We have discovered that HIV hides from defensive systems designed to detect and destroy viral DNA. HIV does this by making viral DNA safely within a structure called the viral capsid. We have shown that the hexameric protein assemblies that make up the capsid transport the nucleotides, used to make DNA, into the capsid through channels in the centre of the hexameric capsid building blocks. We have also shown that the most common type of HIV has uniquely adapted to regulate the channel, allowing it to regulate both DNA synthesis, and capsid disassembly. Finally, we have designed a series of capsid inhibitors that target incoming HIV viral particles and break them open to reveal the DNA inside. This has the effect of, not only potently inhibiting viral infection, but it also allows the infected cell to detect the viral DNA, which is normally hidden, allowing the cell to signal to other uninfected cells that virus is present. Activating innate sensors in this way is expected to generally enhance immunity against viral infection. Overall we have defined a new paradigm for the behaviour of HIV, demonstrated the uniqueness of the most common HIV strain, and designed a class of inhibitors with a novel mechanism of action.