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PEDS Advance Access originally published online on October 29, 2009
Protein Engineering Design and Selection 2009 22(12):753-763; doi:10.1093/protein/gzp060
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Novel regulation of HIV-1 replication and pathogenicity: Rev inhibition of integration

Aviad Levin1, Zvi Hayouka2, Ruth Brack-Werner3, David J. Volsky4, Assaf Friedler2 and Abraham Loyter1,5

1Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences 2Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel 3Institute of Virology, Helmholtz Center Munich - German Research Center for Environmental Health, Ingolstaedter Landstr. 1, D-8576 Neuherberg, Germany 4Molecular Virology Division, St Luke's-Roosevelt Hospital Center, Columbia University, NY 10019, USA

5 To whom correspondence should be addressed. E-mail: loyter{at}cc.huji.ac.il

Following fusion of the human immunodeficiency virus type-1 (HIV-1) with host cells' membrane and reverse transcription of the viral RNA, the resulted cDNA is integrated into the host genome by the viral integrase enzyme (IN). Quantitative estimations have revealed that only 1–2 copies are integrated per infected cell, although many copies of the viral RNA are reverse-transcribed. The molecular mechanism that restricts the integration degree has not, so far, been elucidated. Following integration, expressed partially spliced and unspliced transcripts are exported from the nuclei by the viral Rev protein. Here, we show that in virally infected cells, the Rev interacts with the IN forming a Rev–IN complex and consequently limits the number of integration events. Disruption of the Rev–IN complex by selected IN-derived peptides or infection by a Rev-deficient virus stimulate integration resulting in large numbers of integration event/cell. Conversely, infection of Rev-expression cells blocks integration and inhibits virus production. Increased integration appears to correlate with increased cell death of infected cultures. Our results thus demonstrate a new regulatory function of Rev and probably establish a link between Rev restriction of HIV-1 integration and protection of HIV-1-infected cells from premature cell death.

Keywords: cell death/HIV-1/integrase/integration regulation/Rev

Received September 22, 2009; revised September 22, 2009; accepted September 23, 2009.


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