Resolving HIV-1 transport and host cofactor regulation in the cellular context (360G-Wellcome-311427_Z_24_Z)

HIV remains a huge global health problem but is nonetheless the best studied and best understood of all viruses. Here we propose to take our understanding of how HIV interaction with host cell cofactors regulates infection to a completely new level. We plan four transformative structural biology aims 1) How do HIV capsids interface with the cytoskeleton to travel through the cytoplasm? 2) How do capsids interface with nuclear pores for nuclear entry? 3) How do cofactors regulate capsid uncoating? 4) How do capsids interact with chromatin to target integration? We have developed technical advances in cryo- electron microscopy methods to resolve structures of super-complexes of capsids and cofactors including in infected cells frozen at key moments using CryoCLEM in the CL3 laboratory. We will form and test hypotheses using molecular virology, mutating cells or virus and correlating structural effects with infectivity in an iterative approach. Throughout, we will compare pandemic and non-pandemic HIV to understand and map features associated with pandemic HIV spread. This programme promises to redefine our understanding of how pandemic viral infection is regulated and to provide the most complete atomic level understanding of how host interactions regulate infection for any pathogen to date.