Nucleic Acids Research Advance Access originally published online on November 5, 2007
Nucleic Acids Research 2008 36(1):30-40; doi:10.1093/nar/gkm906
Nucleic Acids Research, 2008, Vol. 36, No. 1 30-40
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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The presence of the TAR RNA structure alters the programmed -1 ribosomal frameshift efficiency of the human immunodeficiency virus type 1 (HIV-1) by modifying the rate of translation initiation
1Département de Biochimie, Université de Montréal, Montréal, Québec, Canada H3T 1J4 and 2Centre de Recherche, Hôpital Ste-Justine, Montréal, Québec, Canada H3T 1C5
*To whom correspondence should be addressed. Tel: 514 343 6316; Fax: 514 343 2210; Email: lea.brakier.gingras{at}umontreal.ca Correspondence may also be addressed to Gerardo Ferbeyre. Tel: 514 343 7571; Fax: 514 343 2210; Email: g.ferbeyre{at}umontreal.ca
Received August 16, 2007. Revised September 12, 2007. Accepted October 6, 2007.
HIV-1 uses a programmed -1 ribosomal frameshift to synthesize the precursor of its enzymes, Gag-Pol. The frameshift efficiency that is critical for the virus replication, is controlled by an interaction between the ribosome and a specific structure on the viral mRNA, the frameshift stimulatory signal. The rate of cap-dependent translation initiation is known to be altered by the TAR RNA structure, present at the 5' and 3' end of all HIV-1 mRNAs. Depending upon its concentration, TAR activates or inhibits the double-stranded RNA-dependent protein kinase (PKR). We investigated here whether changes in translation initiation caused by TAR affect HIV-1 frameshift efficiency. CD4+ T cells and 293T cells were transfected with a dual-luciferase construct where the firefly luciferase expression depends upon the HIV-1 frameshift. Translation initiation was altered by adding TAR in cis or trans of the reporter mRNA. We show that HIV-1 frameshift efficiency correlates negatively with changes in the rate of translation initiation caused by TAR and mediated by PKR. A model is presented where changes in the rate of initiation affect the probability of frameshifting by altering the distance between elongating ribosomes on the mRNA, which influences the frequency of encounter between these ribosomes and the frameshift stimulatory signal.