Molecular mechanisms of HIV-1 restriction by capsid-sensing host cell proteins

During early stages of HIV-1 infection, the viral capsid, a protein shell enclosing the HIV-1 genome, intimately interfaces with the host’s cellular proteins. These essential molecular interactions occur during a pivotal period in the infection process when the virus is highly susceptible to disruptive interventions, thus, representing promising targets for the development of new drugs and therapeutic strategies for HIV-1 prevention and treatment. Among these proteins are host cell defence factors that specifically bind the viral capsid by recognising its surface pattern and disrupting its function, thus potently blocking HIV-1 replication. How the host cell defence proteins sense the incoming viral capsid, however, is not understood.

We aim to determine the common mechanism(s) of capsid pattern sensing by host cell defence proteins using an integrative approach combining structural methods with retrovirology, cell biology and computer simulations. We will also examine the consequences for HIV-1 infection when the host proteins’ pattern-sensing ability is altered. These studies will reveal a major host immune defence mechanism targeting the viral capsid and advance our understanding of viral pattern sensing by the host.

Information derived from our studies will generate a framework for the development of new therapeutic interventions for HIV-1 and other pathogenic viruses.