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

HIV-1’s outer shell, the capsid, is the key that host defence proteins like TrimCyp and MxB grab to stop the virus in its tracks—but exactly how they recognise and latch onto the assembled capsid remains unknown. This project aims to solve that molecular handshake. The problem is that HIV-1 evolves rapidly, and current drugs often lose effectiveness as the virus mutates. Host restriction factors, by contrast, target a part of the capsid that the virus cannot easily change without breaking itself. Understanding how TrimCyp and MxB distinguish the assembled capsid from its individual building blocks could reveal a vulnerability that drugs can exploit. The researcher will combine cryo-electron microscopy and tomography with molecular-dynamics simulations to build atomic-scale models of the capsid bound to these host proteins. Mutational experiments and live-cell imaging during actual infection will then confirm which interfaces matter most. If successful, this fundamental science could guide the design of small molecules that mimic or enhance the host’s pattern-recognition ability, creating a new class of antivirals that block HIV-1 replication at its earliest stage. No immediate practical application exists yet, but similar structural studies of viral capsids have previously enabled the development of protease inhibitors and capsid-targeting drugs now in clinical use.