What is special about pandemic HIV-1? How capsid cofactor interactions regulate DNA synthesis, innate immune detection and pandemic potential (360G-Wellcome-214344_Z_18_Z)

The HIV-1 pandemic originates from one of many zoonotic simian lentiviruses. A key unanswered question is: what is special about pandemic HIV-1? Our previous work suggests a pivotal role for lentiviral capsids as molecular machines that determine innate immune evasion capacity and pandemic potential. Lentiviral capsids simultaneously regulate viral DNA synthesis, viral genome uncoating, nuclear entry and integration targeting, through coordinated and dynamic recruitment of host cofactors. The goal of this application is to understand how capsids work by considering the structural changes that result from interactions with known and novel cellular cofactors and drugs, the biological consequences of these changes and how they drive infection, zoonosis and pandemicity. We propose three aims that integrate structural, single-molecule and chemical biology with comparative virology. In aim one we will use state of the art structural approaches to understand cofactor capsid interactions. In aim two we will determine how host cofactors manipulate capsid function to temporally and spatially orchestrate DNA synthesis and genome uncoating to facilitate evasion of innate immunity. In aim three we will use our novel CA inhibitor series as tools to probe capsid function and to develop a new paradigm for treatment of infection.