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Clinical and Vaccine Immunology, October 2007, p. 1266-1273, Vol. 14, No. 10
1071-412X/07/$08.00+0     doi:10.1128/CVI.00169-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Selective Pressures of HLA Genotypes and Antiviral Therapy on Human Immunodeficiency Virus Type 1 Sequence Mutation at a Population Level

Golo Ahlenstiel,^1, Kirsten Roomp,^2, Martin Däumer,³ Jacob Nattermann,¹ Martin Vogel,¹ Jürgen K. Rockstroh,¹ Niko Beerenwinkel,⁴ Rolf Kaiser,³ Hans-Dieter Nischalke,¹ Tilman Sauerbruch,¹ Thomas Lengauer,² Ulrich Spengler,^1* on behalf of the Kompetenznetz HIV/AIDS

Department of Internal Medicine I, University of Bonn, 53105 Bonn, Germany,¹ Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123 Saarbrücken, Germany,² Institute of Virology, University of Cologne, 50935 Cologne, Germany,³ Department of Mathematics, University of California, Berkeley, California⁴

Received 18 April 2007/ Returned for modification 31 May 2007/ Accepted 2 August 2007

The objective of this study was a comprehensive analysis of the immune-driven evolution of viruses of human immunodeficiency virus type 1 (HIV-1) clade B in a large patient cohort treated at a single hospital in Germany and its implications for antiretroviral therapy. We examined the association of the HLA-A, HLA-B, and HLA-DRB1 alleles with the emergence of mutations in the complete protease gene and the first 330 codons of the reverse transcriptase (RT) gene of HIV-1, studying their distribution and persistence and their impact on antiviral drug therapy. The clinical data for 179 HIV-infected patients, the results of HLA genotyping, and virus sequences were analyzed using a variety of statistical approaches. We describe new HLA-associated mutations in both viral protease and RT, several of which are associated with HLA-DRB1. The mutations reported are remarkably persistent within our cohort, developing more slowly in a minority of patients. Interestingly, several HLA-associated mutations occur at the same positions as drug resistance mutations in patient viruses, where the viral sequence was acquired before exposure to these drugs. The influence of HLA on thymidine analogue mutation pathways was not observed. We were able to confirm immune-driven selection pressure by major histocompatibility complex (MHC) class I and II alleles through the identification of HLA-associated mutations. HLA-B alleles were involved in more associations (68%) than either HLA-A (23%) or HLA-DRB1 (9%). As several of the HLA-associated mutations lie at positions associated with drug resistance, our results indicate possible negative effects of HLA genotypes on the development of HIV-1 drug resistance.

Published ahead of print on 22 August 2007.

Both authors contributed equally to this work.

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