Novel regulation of HIV-1 replication and pathogenicity: Rev inhibition of integration.
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.
Levin
Aviad
A
Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Hayouka
Zvi
Z
Brack-Werner
Ruth
R
Volsky
David J
DJ
Friedler
Assaf
A
Loyter
Abraham
A
D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004279:DNA, Viral / Q000032:analysis; D015694:Gene Products, rev / Q000502:physiology; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D016133:Polymerase Chain Reaction; D016662:Virus Integration
D017931:DNA Primers; D004279:DNA, Viral; D015694:Gene Products, rev