HIV-1 capsid is involved in post-nuclear entry steps

Nan Yu Chen, Lihong Zhou, Paul J. Gane, Silvana Opp, Neil J. Ball, Giuseppe Nicastro, Madeleine Zufferey, Cindy Buffone, Jeremy Luban, David Selwood, Felipe Diaz-Griffero, Ian Taylor, Ariberto Fassati

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Background: HIV-1 capsid influences viral uncoating and nuclear import. Some capsid is detected in the nucleus but it is unclear if it has any function. We reported that the antibiotic Coumermycin-A1 (C-A1) inhibits HIV-1 integration and that a capsid mutation confers resistance to C-A1, suggesting that capsid might affect post-nuclear entry steps. Results: Here we report that C-A1 inhibits HIV-1 integration in a capsid-dependent way. Using molecular docking, we identify an extended binding pocket delimited by two adjacent capsid monomers where C-A1 is predicted to bind. Isothermal titration calorimetry confirmed that C-A1 binds to hexameric capsid. Cyclosporine washout assays in Jurkat CD4+ T cells expressing engineered human TRIMCyp showed that C-A1 causes faster and greater escape from TRIMCyp restriction. Sub-cellular fractionation showed that small amounts of capsid accumulated in the nuclei of infected cells and C-A1 reduced the nuclear capsid. A105S and N74D capsid mutant viruses did not accumulate capsid in the nucleus, irrespective of C-A1 treatment. Depletion of Nup153, a nucleoporin located at the nuclear side of the nuclear pore that binds to HIV-1 capsid, made the virus less susceptible to TRIMCyp restriction, suggesting that Nup153 may help maintain some integrity of the viral core in the nucleus. Furthermore C-A1 increased binding of CPSF6, a nuclear protein, to capsid. Conclusions: Our results indicate that capsid is involved in post-nuclear entry steps preceding integration.

Original languageEnglish (US)
Article number28
JournalRetrovirology
Volume13
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

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Keywords

  • Capsid
  • Coumermycin-A1
  • HIV-1
  • Integration
  • Nucleoporins
  • Nucleus
  • Nup153
  • Uncoating

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

Cite this

Chen, N. Y., Zhou, L., Gane, P. J., Opp, S., Ball, N. J., Nicastro, G., ... Fassati, A. (2016). HIV-1 capsid is involved in post-nuclear entry steps. Retrovirology, 13(1), [28]. https://doi.org/10.1186/s12977-016-0262-0