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Journal of Virology, October 2007, p. 11322-11331, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.00162-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Interaction of APOBEC3G with Human Immunodeficiency Virus Type 1 Nucleocapsid Inhibits tRNA3Lys Annealing to Viral RNA{triangledown}

Fei Guo,1 Shan Cen,1,2 Meijuan Niu,1 Yiliang Yang,1 Robert J. Gorelick,4 and Lawrence Kleiman1,2,3*

Lady Davis Institute for Medical Research and McGill AIDS Centre, Jewish General Hospital,1 Departments of Medicine,2 Microbiology & Immunology, McGill University, Montreal, Quebec, Canada H3T 1E2,3 AIDS Vaccine Program, Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 217024

Received 24 January 2007/ Accepted 21 July 2007

Human immunodeficiency virus type 1 (HIV-1) containing human APOBEC3G (hA3G) has a reduced ability to produce viral DNA in newly infected cells. At least part of this hA3G-facilitated inhibition is due to a cytidine deamination-independent reduction in the ability to initiate reverse transcription. HIV-1 nucleocapsid (NCp7) is required both for the incorporation of hA3G into virions and for the annealing between viral RNA and tRNA3Lys, the primer tRNA for reverse transcription. Herein we present evidence that the interaction of hA3G with nucleocapsid is required for the inhibition of reverse transcription initiation. A tRNA3Lys priming complex was produced in vitro by the NCp7-facilitated annealing of tRNA3Lys to synthetic viral RNA in the absence or presence of hA3G. The effect of hA3G on the annealing of tRNA3Lys to viral RNA and the ability of tRNA3Lys to initiate reverse transcription was measured. Our results show the following. (i) Electrophoretic band shift and primer binding site assays show that hA3G reduces the annealing of tRNA3Lys 44 and 60%, respectively, but does not disrupt the annealed complex once formed. (ii) hA3G inhibits tRNA3Lys priming 70 to 80%. (iii) Inhibition of tRNA3Lys priming by hA3G requires an interaction between hA3G and NCp7 during annealing. Thus, annealing of tRNA3Lys is insensitive to hA3G inhibition when facilitated by a zinc finger mutant of NCp7 unable to interact with hA3G. NCp7-independent annealing of DNA to viral RNA also is insensitive to hA3G inhibition. These results indicate that hA3G does not sterically block tRNA3Lys annealing by binding to viral RNA. Annealing and priming are not affected by another RNA binding protein, QKI-6.

* Corresponding author. Mailing address: Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote St. Catherine Rd., Montreal, Quebec, Canada H3T 1E2. Phone: (514) 340-8260. Fax: (514) 340-7502. E-mail: lawrence.kleiman{at}mcgill.ca

{triangledown} Published ahead of print on 1 August 2007.

Journal of Virology, October 2007, p. 11322-11331, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.00162-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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