National Institute of Allergy and Infectious Diseases 5U54AI170791-05

Project 2. Immune evasion, trafficking, and nuclear import

This NIH-funded research project by University of Pittsburgh aims to elucidate the atomic-level structural and dynamic interactions of HIV-1 capsid with host proteins involved in immune evasion, intracellular trafficking, and nuclear import to inform development of new capsid inhibitors.

Description

The HIV-1 capsid acts as the primary interface between the virus and the cell during viral ingress and nuclear entry. The capsid is critically involved throughout all steps of the replication cycle, including uncoating, recognition by host factors, trafficking along microtubules, nuclear import, and genome integration. Recent research revealed that HIV-1 capsid hijacks microtubule motors dynein and kinesin for its journey towards the nucleus, and an intact capsid can traverse the cellular nuclear pore complex (NPC). These data significantly impact our views of HIV-1 cytoplasmic transport, nuclear import, intranuclear transport, and uncoating, and indicate that capsid is a key player in HIV-1 ingress. However, atomic-level understanding of capsid recognition by host factors is lacking, and it is unclear how the dynamic exchange of factors occurs during viral movement from the cell periphery to the site of integration inside the nucleus. The overall goal of this project is to fill these knowledge gaps by providing critical structural and dynamic information on capsid’s engagement in immune evasion, trafficking, and integration. The proposed studies are an integrated effort from seven PCHPI investigators and four cores (CryoEM/ET, NMR, Computational, and HIV Virology). Specifically, the project aims to: Elucidate the interactions of HIV-1 capsid with host innate immune proteins, including MxB and TRIM5α/TRIMCyp. Determine the interactions between HIV-1 capsid and intracellular trafficking proteins, including kinesin-1/FEZ1 and dynein/dynactin/BICD2, and microtubules. Define the dynamics of HIV-1 capsid interactions with host dependency factors involved in nuclear import, including the nucleoporins Nup358 and Nup153 and the host factors CPSF6 and SUN1/2. These results will provide an unprecedented atomic-level structural and dynamic view of capsid’s interactions with host proteins and could guide the development of new clinically relevant capsid inhibitors.

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