Multidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization

Anna T. Gres, Karen A. Kirby, William M. McFadden, Haijuan Du, Dandan Liu, Chaoyi Xu, Alexander J. Bryer, Juan R. Perilla, Jiong Shi, Christopher Aiken, Xiaofeng Fu, Peijun Zhang, Ashwanth C. Francis, Gregory B. Melikyan and Stefan G. Sarafianos ()
Additional contact information
Anna T. Gres: University of Missouri
Karen A. Kirby: Emory University School of Medicine
William M. McFadden: Emory University School of Medicine
Haijuan Du: Emory University School of Medicine
Dandan Liu: University of Missouri
Chaoyi Xu: University of Delaware
Alexander J. Bryer: University of Delaware
Juan R. Perilla: University of Delaware
Jiong Shi: Vanderbilt University Medical Center
Christopher Aiken: Vanderbilt University Medical Center
Xiaofeng Fu: University of Pittsburgh, School of Medicine
Peijun Zhang: University of Pittsburgh, School of Medicine
Ashwanth C. Francis: Florida State University
Gregory B. Melikyan: Children’s Healthcare of Atlanta
Stefan G. Sarafianos: Emory University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract HIV-1 capsid (CA) stability is important for viral replication. E45A and P38A mutations enhance and reduce core stability, thus impairing infectivity. Second-site mutations R132T and T216I rescue infectivity. Capsid lattice stability was studied by solving seven crystal structures (in native background), including P38A, P38A/T216I, E45A, E45A/R132T CA, using molecular dynamics simulations of lattices, cryo-electron microscopy of assemblies, time-resolved imaging of uncoating, biophysical and biochemical characterization of assembly and stability. We report pronounced and subtle, short- and long-range rearrangements: (1) A38 destabilized hexamers by loosening interactions between flanking CA protomers in P38A but not P38A/T216I structures. (2) Two E45A structures showed unexpected stabilizing CANTD-CANTD inter-hexamer interactions, variable R18-ring pore sizes, and flipped N-terminal β-hairpin. (3) Altered conformations of E45Aa α9-helices compared to WT, E45A/R132T, WTPF74, WTNup153, and WTCPSF6 decreased PF74, CPSF6, and Nup153 binding, and was reversed in E45A/R132T. (4) An environmentally sensitive electrostatic repulsion between E45 and D51 affected lattice stability, flexibility, ion and water permeabilities, electrostatics, and recognition of host factors.

Date: 2023
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DOI: 10.1038/s41467-023-41197-7

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