Project 2. Immune evasion, trafficking, and nuclear import

Project 2 – Immune evasion, trafficking and nuclear import
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, we will i)
elucidate the interactions of HIV-1 capsid with host innate immune proteins, including MxB and
TRIM5α/TRIMCyp; ii) determine the interactions between HIV-1 capsid and intracellular trafficking proteins,
including kinesin-1/FEZ1 and dynein/dynactin/BICD2, and microtubules; and iii) 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. Our results will provide 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.

Grant Number: 5U54AI170791-04
NIH Institute/Center: NIH
Principal Investigator: Zandrea Ambrose