Nucleocytoplasmic shuttling of HIV-1 integrase is controlled by the viral Rev protein

Aviad Levin, Zvi Hayouka, Assaf Friedler, Abraham Loyter*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

In the current study we show that the Rev protein of Human Immunodeficiency Virus type 1 (HIV-1) inhibits nuclear import and mediates nuclear export of the HIV-1 integrase (IN) protein, which catalyzes integration of the viral cDNA. Interaction between IN and Rev in virus infected cells, resulting in the formation of a Rev-IN complex, has been previously described by us. Here we show that nuclear import of the IN, is inhibited by early expressed Rev. No nuclear import of IN was observed when Rev-overexpressing cells were infected by wild-type HIV-1. Similarly, no translocation of IN into nuclei was observed in the presence of Rev-derived peptides. On the other hand, massive nuclear import was observed following infection by a Δ Rev virus or in the presence of peptides that promote dissociation of the Rev-IN complex. Our results show that IN is only transiently present within the nuclei of infected cells. Treatment of infected cells with leptomycin B caused nuclear retention of the Rev-IN complex. Removal of the leptomycin from these treated cells resulted in nuclear export of both Rev and IN. On the other hand, disruption of the nuclear located Rev-IN complex resulted in export of only the Rev protein indicating Rev-mediated nuclear export of IN. Our results suggest the involvement of Rev in regulating the integration process by limiting the number of integration events per cell despite the presence of numerous copies of viral cDNA.

Original languageAmerican English
JournalNucleus
Volume1
Issue number2
DOIs
StatePublished - 2010

Bibliographical note

Funding Information:
This work was supported by the Israeli Science Foundation (A. Loyter) and by a starting grant from the European Research Council (ERC) (to A.F.). The authors are imbedded to Prof. Z. Debyser (Molecular Medicine, K.U. Leuven, Flanders, Belgium) and Prof. Poeschla (Department of Molecular Medicine, Mayo Foundation, Rochester MN) for the LEDGF/p75 knock-down cells. The authors also imbedded to Prof. B. Berkhout (Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, The Netherlands) and Prof. A. Engelman (Department of Cancer Immunology and AIDS Dana-Farber Cancer Institute and Division of AIDS, Harvard Medical School, Boston, MA) for the mutated viral strands.

Keywords

  • HIV-1
  • Integrase
  • Nuclear export
  • Nuclear import
  • Peptides
  • Rev

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