Molecular mechanisms of HIV-1 restriction by capsid-sensing host cell proteins (360G-Wellcome-206422_Z_17_Z)

Infections by retroviruses, such as HIV-1, critically depend on the viral capsid. Many host cell defence proteins, including restriction factors Trim5alpha, TrimCyp and MxB, target the viral capsid at the early stages of infection and potently inhibit virus replication. These restriction factors appear to function through a remarkable capsid pattern sensing ability that specifically recognizes the assembled capsid, but not the individual capsid protein. Using an integrative and multidisciplinary approach, I aim to determine the molecular interactions between the viral capsid and host restriction factors, TrimCyp and MxB, that underpin their capsid pattern-sensing capability and ability to inhibit HIV-1 replication. Specifically, I will combine cryoEM and cryoET with all-atom molecular-dynamics simulations to obtain high-resolution structures and atomic models of the capsid and host protein complexes (in vitro), together with mutational and functional analysis as well as correlative light and cryoET imaging of viral infection process (in vivo and in situ), to reveal the essential interfaces in their 3D organization for HIV-1 capsid recognition and inhibition of HIV-1 infection. Information derived from our studies will allow to design more robust therapeutic agents to block HIV-1 replication by strengthening the pattern recognition feature.