Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket

• Published in: mBio Vol. 10; no. 2
• Main Authors: Craveur, Pierrick, Gres, Anna T, Kirby, Karen A, Liu, Dandan, Hammond, John A, Deng, Yisong, Forli, Stefano, Goodsell, David S, Williamson, James R, Sarafianos, Stefan G, Olson, Arthur J
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 12-03-2019
• Subjects: BASIC BIOLOGICAL SCIENCES; capsid; Capsid - metabolism; Capsid - ultrastructure; capsid assembly; computer modeling; Crystallography, X-Ray; DNA Mutational Analysis; HIV Core Protein p24 - metabolism; HIV-1 - physiology; human immunodeficiency virus; Microscopy, Electron, Transmission; Molecular Dynamics Simulation; Protein Binding; Protein Interaction Mapping; Protein Multimerization; Therapeutics and Prevention; Virus Assembly; X-ray crystallography; X-ray crystallography; human immunodeficiency virus; computer modeling; capsid; capsid assembly
• ISSN: 2161-2129; 2150-7511; 2150-7511
• DOI: 10.1128/mbio.02858-18

HIV-1 capsid protein (CA) plays critical roles in both early and late stages of the viral replication cycle. Mutagenesis and structural experiments have revealed that capsid core stability significantly affects uncoating and initiation of reverse transcription in host cells. This has led to efforts in developing antivirals targeting CA and its assembly, although none of the currently identified compounds are used in the clinic for treatment of HIV infection. A specific interaction that is primarily present in pentameric interfaces in the HIV-1 capsid core was identified and is reported to be important for CA assembly. This is shown by multidisciplinary characterization of CA site-directed mutants using biochemical analysis of virus-like particle formation, transmission electron microscopy of
assembly, crystallographic studies, and molecular dynamic simulations. The data are consistent with a model where a hydrogen bond between CA residues E28 and K30' from neighboring N-terminal domains (CA
s) is important for CA pentamer interactions during core assembly. This pentamer-preferred interaction forms part of an
-terminal
omain
nterface (NDI) pocket that is amenable to antiviral targeting.
Precise assembly and disassembly of the HIV-1 capsid core are key to the success of viral replication. The forces that govern capsid core formation and dissociation involve intricate interactions between pentamers and hexamers formed by HIV-1 CA. We identified one particular interaction between E28 of one CA and K30' of the adjacent CA that appears more frequently in pentamers than in hexamers and that is important for capsid assembly. Targeting the corresponding site could lead to the development of antivirals which disrupt this interaction and affect capsid assembly.