Nuclear pore heterogeneity influences HIV-1 infection and the antiviral activity of MX2

Elife. 2018 Aug 7:7:e35738. doi: 10.7554/eLife.35738.

Abstract

HIV-1 accesses the nuclear DNA of interphase cells via a poorly defined process involving functional interactions between the capsid protein (CA) and nucleoporins (Nups). Here, we show that HIV-1 CA can bind multiple Nups, and that both natural and manipulated variation in Nup levels impacts HIV-1 infection in a manner that is strikingly dependent on cell-type, cell-cycle, and cyclophilin A (CypA). We also show that Nups mediate the function of the antiviral protein MX2, and that MX2 can variably inhibit non-viral NLS function. Remarkably, both enhancing and inhibiting effects of cyclophilin A and MX2 on various HIV-1 CA mutants could be induced or abolished by manipulating levels of the Nup93 subcomplex, the Nup62 subcomplex, NUP88, NUP214, RANBP2, or NUP153. Our findings suggest that several Nup-dependent 'pathways' are variably exploited by HIV-1 to target host DNA in a cell-type, cell-cycle, CypA and CA-sequence dependent manner, and are differentially inhibited by MX2.

Keywords: HIV; cell biology; infectious disease; integration; microbiology; nuclear import; nucleoporin; virus.

Publication types

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

MeSH terms

  • Antiviral Agents / metabolism*
  • Capsid Proteins / metabolism
  • Cell Line
  • HIV Infections / pathology*
  • HIV Infections / virology*
  • HIV-1 / growth & development*
  • HIV-1 / immunology*
  • Humans
  • Myxovirus Resistance Proteins / metabolism*
  • Nuclear Pore / metabolism*
  • Nuclear Pore Complex Proteins / metabolism
  • Protein Binding

Substances

  • Antiviral Agents
  • Capsid Proteins
  • MX2 protein, human
  • Myxovirus Resistance Proteins
  • Nuclear Pore Complex Proteins