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Journal of Virology, August 2005, p. 10601-10607, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10601-10607.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Ordered Processing of the Human Immunodeficiency Virus Type 1 GagPol Precursor Is Influenced by the Context of the Embedded Viral Protease

Steven C. Pettit,1 Jose C. Clemente,5 Jennifer A. Jeung,5 Ben M. Dunn,5 and Andrew H. Kaplan1,2,3,4*

Departments of Medicine,1 Microbiology and Immunology,2 Lineberger Comprehensive Cancer Center,3 Center for Infectious Diseases, University of North Carolina School of Medicine, Campus Box 7290, Chapel Hill, North Carolina 27599-7290,4 Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, P.O. Box 100245, Gainesville, Florida 32610-02455

Received 7 February 2005/ Accepted 18 April 2005

Ordered and accurate processing of the human immunodeficiency virus type 1 (HIV-1) GagPol polyprotein precursor by a virally encoded protease is an indispensable step in the appropriate assembly of infectious viral particles. The HIV-1 protease (PR) is a 99-amino-acid enzyme that is translated as part of the GagPol precursor. Previously, we have demonstrated that the initial events in precursor processing are accomplished by the PR domain within GagPol in cis, before it is released from the polyprotein. Despite the critical role that ordered processing of the precursor plays in viral replication, the forces that define the order of cleavage remain poorly understood. Using an in vitro assay in which the full-length HIV-1 GagPol is processed by the embedded PR, we examined the effect of PR context (embedded within GagPol versus the mature 99-amino-acid enzyme) on precursor processing. Our data demonstrate that the PR domain within GagPol is constrained in its ability to cleave some of the processing sites in the precursor. Further, we find that this constraint is dependent upon the presence of a proline as the initial amino acid in the embedded PR; substitution of an alanine at this position produces enhanced cleavage at additional sites when the precursor is processed by the embedded, but not the mature, PR. Overall, our data support a model in which the selection of processing sites and the order of precursor processing are defined, at least in part, by the structure of GagPol itself.

* Corresponding author. Mailing address: Department of Medicine, 705 MEJ, Campus Box 7290, University of North Carolina, Chapel Hill, NC 27599-7290. Phone: (919) 843-0693. Fax: (919) 962-8103. E-mail: akaplan{at}med.unc.edu.

Journal of Virology, August 2005, p. 10601-10607, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10601-10607.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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