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Journal of Virology, November 2008, p. 11476-11479, Vol. 82, No. 22
0022-538X/08/$08.00+0     doi:10.1128/JVI.00726-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Active-Site Mutations in the South African Human Immunodeficiency Virus Type 1 Subtype C Protease Have a Significant Impact on Clinical Inhibitor Binding: Kinetic and Thermodynamic Study{triangledown}

Salerwe Mosebi,1 Lynn Morris,2 Heini W. Dirr,1 and Yasien Sayed1*

Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, I Jan Smuts Avenue, Johannesburg, 2050,1 AIDS Virus Research Unit, National Institute for Communicable Diseases, Private Bag X4, Sandringham 2131, Johannesburg, South Africa2

Received 2 April 2008/ Accepted 28 August 2008

Human immunodeficiency virus (HIV) infections in sub-Saharan Africa represent about 56% of global infections. Study of active-site mutations (the V82A single mutation and the V82F I84V double mutation) in the less-studied South African HIV type 1 subtype C (C-SA) protease indicated that neither mutation had a significant impact on the proteolytic functioning of the protease. However, the binding affinities of, and inhibition by, saquinavir, ritonavir, indinavir, and nelfinavir were weaker for each variant than for the wild-type protease, with the double mutant exhibiting the most dramatic change. Therefore, our results show that the C-SA V82F I84V double mutation decreased the binding affinities of protease inhibitors to levels significantly lower than that required for effective inhibition.

* Corresponding author. Mailing address: Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, I Jan Smuts Avenue, Johannesburg 2050, South Africa. Phone: (27-11) 717-6350. Fax: (27-11) 717-6351. E-mail: yasien.sayed{at}wits.ac.za

{triangledown} Published ahead of print on 3 September 2008.

Journal of Virology, November 2008, p. 11476-11479, Vol. 82, No. 22
0022-538X/08/$08.00+0     doi:10.1128/JVI.00726-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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