Transportin-1 binds to the HIV-1 capsid via a nuclear localization signal and triggers uncoating

Nat Microbiol. 2019 Nov;4(11):1840-1850. doi: 10.1038/s41564-019-0575-6. Epub 2019 Oct 14.


The initial steps of HIV replication in host cells prime the virus for passage through the nuclear pore and drive the establishment of a productive and irreparable infection1,2. The timely release of the viral genome from the capsid-referred to as uncoating-is emerging as a critical parameter for nuclear import, but the triggers and mechanisms that orchestrate these steps are unknown. Here, we identify β-karyopherin Transportin-1 (TRN-1) as a cellular co-factor of HIV-1 infection, which binds to incoming capsids, triggers their uncoating and promotes viral nuclear import. Depletion of TRN-1, which we characterized by mass spectrometry, significantly reduced the early steps of HIV-1 infection in target cells, including primary CD4+ T cells. TRN-1 bound directly to capsid nanotubes and induced dramatic structural damage, indicating that TRN-1 is necessary and sufficient for uncoating in vitro. Glycine 89 on the capsid protein, which is positioned within a nuclear localization signal in the cyclophilin A-binding loop, is critical for engaging the hydrophobic pocket of TRN-1 at position W730. In addition, TRN-1 promotes the efficient nuclear import of both viral DNA and capsid protein. Our study suggests that TRN-1 mediates the timely release of the HIV-1 genome from the capsid protein shell and efficient viral nuclear import.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Binding Sites
  • CD4-Positive T-Lymphocytes / metabolism
  • Capsid / chemistry
  • Capsid / metabolism
  • Capsid Proteins / chemistry*
  • Capsid Proteins / metabolism*
  • Gene Deletion
  • HEK293 Cells
  • HIV Infections / genetics
  • HIV Infections / metabolism*
  • HIV Infections / virology
  • HIV-1 / metabolism
  • HIV-1 / physiology*
  • HeLa Cells
  • Humans
  • Mass Spectrometry
  • Models, Molecular
  • Nuclear Localization Signals
  • Protein Binding
  • Protein Conformation
  • RNA, Viral / metabolism
  • Virus Uncoating
  • beta Karyopherins / chemistry*
  • beta Karyopherins / genetics
  • beta Karyopherins / metabolism*


  • Capsid Proteins
  • Nuclear Localization Signals
  • RNA, Viral
  • TNPO1 protein, human
  • beta Karyopherins