Diverse Functions of HIV-1 Capsid During Postentry Events

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Project Summary The HIV-1 capsid, which encloses viral and host components essential for establishing infection, influences every post-entry step, including reverse transcription, nuclear entry and integration targeting. These capsid- mediated events are governed by HIV-1 uncoating, a process in which the conical core sheds viral capsid proteins (CA) and transforms into reverse transcription complexes and then pre-integration complexes. Uncoating of the viral capsid is regulated by both core stability and capsid-binding host cofactors. Much remains to be learned about how the uncoating process is coordinated to facilitate viral propagation. Temporal deviations from the normal course of capsid disassembly (delayed or accelerated uncoating) by antiviral factors or pharmacological manipulation can severely impair viral infectivity. However, it still remains unclear precisely how intrinsic core stability affects capsid disassembly and downstream events. Our preliminary studies have identified a natural HIV-1 strain that appears to alter core stability without compromising viral fitness. In Aim 1, we will characterize a broad range of biological properties of this unique variant and also exploit core-destabilizing activity of capsid-targeting antivirals as a tool to study capsid stability. Current models posit that core disassembly impacts innate sensing of HIV-1 DNA but mechanistic details have yet to be elucidated. In Aim 2, we propose to examine how perturbation of uncoating by manipulating core stability and capsid interactions with host proteins affects innate immune responses. Capsid uncoating also plays roles in nuclear events, such as nuclear import and integration targeting. In Aim 3, we will address how these events are functionally linked and contribute to optimal viral growth by using various experimental approaches, including novel high-throughput single-cell assays.