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J. Biol. Chem., Vol. 280, Issue 28, 26018-26023, July 15, 2005

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Inhibition of Cellular HIV-1 Protease Activity by Lysyl-tRNA Synthetase^*

Fei Guo, Juliana Gabor, Shan Cen, Kimberly Hu, Andrew J. Mouland¶||, and Lawrence Kleiman¶**

From the Lady Davis Institute for Medical Research and McGill AIDS Centre, Jewish General Hospital, Montreal, Quebec H3T 1E2, and the Departments of ^¶Medicine and Microbiology and Immunology, McGill University, Montreal, Quebec H3T 1E2, Canada

During early assembly of human immunodeficiency virus type 1 (HIV-1), an assembly complex is formed, the components of which include genomic RNA, Gag, GagPol, tRNA^Lys, and lysyl tRNA synthetase (LysRS). Directly increasing or decreasing cellular expression of LysRS results in corresponding changes in viral infectivity and in the viral concentrations of LysRS, tRNA^Lys, and, surprisingly, reverse transcriptase (RT). Since altering the cellular expression of LysRS does not lead to a change in the incorporation of the RT precursor protein, GagPol, in protease-negative HIV-1, we propose that the altered viral content of RT resulting from alterations in cellular LysRS concentration results from the ability of LysRS to inhibit premature activation of Gag-Pol viral protease within the complex. Supporting this hypothesis, we find that increases and decreases in cellular LysRS expression are accompanied by 5–8-fold increases and 5-fold decreases, respectively, in the cytoplasmic proteolysis of Gag and GagPol to mature viral proteins. Using a novel bioluminescence resonance energy transfer assay to directly measure HIV-1 protease activity in vivo also indicates that the overexpression of LysRS in the cell reduces viral protease activity.

Received for publication, March 4, 2005 , and in revised form, April 20, 2005.

^* This work was supported in part by grants from the National Institutes of Health and the Canadian Institutes for Health Research (CIHR) and the Canadian Foundation for Innovation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Recipient of a CIHR New Investigator Award.

^** To whom correspondence should be addressed: Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote St. Catherine Rd., Montreal, Quebec, Canada H3T 1E2. Tel.: 514-340-8260; Fax: 514-340-7502; E-mail: lawrence.kleiman{at}mcgill.ca.

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