MxB Restricts HIV-1 by Targeting the Tri-hexamer Interface of the Viral Capsid

Structure. 2019 Aug 6;27(8):1234-1245.e5. doi: 10.1016/j.str.2019.04.015. Epub 2019 May 30.

Abstract

The human antiviral protein MxB is a restriction factor that fights HIV infection. Previous experiments have demonstrated that MxB targets the HIV capsid, a protein shell that protects the viral genome. To make the conical-shaped capsid, HIV CA proteins are organized into a lattice composed of hexamer and pentamer building blocks, providing many interfaces for host proteins to recognize. Through extensive biochemical and biophysical studies and molecular dynamics simulations, we show that MxB is targeting the HIV capsid by recognizing the region created at the intersection of three CA hexamers. We are further able to map this interaction to a few CA residues, located in a negatively charged well at the interface between the three CA hexamers. This work provides detailed residue-level mapping of the targeted capsid interface and how MxB interacts. This information could inspire the development of capsid-targeting therapies for HIV.

Keywords: HIV; MxB; capsid; molecular dynamics; pattern-sensing; simulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Capsid / chemistry*
  • Capsid / metabolism*
  • HIV Infections / metabolism
  • HIV Infections / virology
  • HIV-1 / genetics
  • HIV-1 / metabolism*
  • Host-Pathogen Interactions
  • Humans
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Mutation
  • Myxovirus Resistance Proteins / chemistry*
  • Myxovirus Resistance Proteins / genetics
  • Myxovirus Resistance Proteins / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization

Substances

  • MX2 protein, human
  • Myxovirus Resistance Proteins