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Journal of Virology, March 2007, p. 2887-2898, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.01547-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Dual Selection Pressure by Drugs and HLA Class I-Restricted Immune Responses on Human Immunodeficiency Virus Type 1 Protease{triangledown} ,{dagger}

Sandra M. Mueller,1,4* Birgit Schaetz,1,4 Kathrin Eismann,1 Silke Bergmann,1 Michael Bauerle,1 Matthias Schmitt-Haendle,1 Hauke Walter,2,4 Barbara Schmidt,2 Klaus Korn,2 Heinrich Sticht,3 Bernd Spriewald,1 Ellen G. Harrer,1 and Thomas Harrer1,4

Department of Medicine III, University Hospital Erlangen, Krankenhausstr. 12, 91054 Erlangen, Germany,1 Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany,2 Institute of Biochemistry, Emil-Fischer-Center, University of Erlangen-Nuremberg, Erlangen, Germany,3 German Competence Network on HIV/AIDS4

Received 19 July 2006/ Accepted 21 December 2006

To determine the influence of human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells on the development of drug resistance mutations in the HIV-1 protease, we analyzed protease sequences from viruses from a human leukocyte antigen class I (HLA class I)-typed cohort of 94 HIV-1-positive individuals. In univariate statistical analyses (Fisher's exact test), minor and major drug resistance mutations as well as drug-associated polymorphisms showed associations with HLA class I alleles. All correlations with P values of 0.05 or less were considered to be relevant without corrections for multiple tests. A subset of these observed correlations was experimentally validated by enzyme-linked immunospot assays, allowing the definition of 10 new epitopes recognized by CD8+ T cells from patients with the appropriate HLA class I type. Several drug resistance-associated mutations in the protease acted as escape mutations; however, cells from many patients were still able to generate CD8+ T cells targeting the escape mutants. This result presumably indicates the usage of different T-cell receptors by CD8+ T cells targeting these epitopes in these patients. Our results support a fundamental role for HLA class I-restricted immune responses in shaping the sequence of the HIV-1 protease in vivo. This role may have important clinical implications both for the understanding of drug resistance pathways and for the design of therapeutic vaccines targeting drug-resistant HIV-1.

* Corresponding author. Mailing address: Immunodeficiency Center of the Department of Medicine III, University Hospital Erlangen, Krankenhausstr. 12, 91054 Erlangen, Germany. Phone: 499131-8539107. Fax: 499131-8535776. E-mail: Sandra.Mueller{at}med3.imed.uni-erlangen.de.

{triangledown} Published ahead of print on 3 January 2007.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, March 2007, p. 2887-2898, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.01547-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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