title: Selective pressures of HLA genotypes and antiviral therapy on human immunodeficiency virus type 1 sequence mutation at a population level.
abstract: 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.
authors: Department of Internal Medicine I, University of Bonn, 53105 Bonn, Germany.
authors: Golo
authors: G
authors: Ahlenstiel
authors: Kirsten
authors: K
authors: Roomp
authors: Martin
authors: M
authors: Däumer
authors: Jacob
authors: J
authors: Nattermann
authors: Martin
authors: M
authors: Vogel
authors: Jürgen K
authors: JK
authors: Rockstroh
authors: Niko
authors: N
authors: Beerenwinkel
authors: Rolf
authors: R
authors: Kaiser
authors: Hans-Dieter
authors: HD
authors: Nischalke
authors: Tilman
authors: T
authors: Sauerbruch
authors: Thomas
authors: T
authors: Lengauer
authors: Ulrich
authors: U
authors: Spengler
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D001483:Base Sequence / Q000235:genetics; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics / Q000276:immunology; D019143:Evolution, Molecular; D005260:Female; D005838:Genotype; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012641:Selection, Genetic
chemical_list: D019380:Anti-HIV Agents; D006680:HLA Antigens; D054303:HIV Reverse Transcriptase
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