title: Dual selection pressure by drugs and HLA class I-restricted immune responses on human immunodeficiency virus type 1 protease.
abstract: 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.
authors.affiliation: Immunodeficiency Center of the Department of Medicine III, University Hospital Erlangen, Krankenhausstrasse 12, 91054 Erlangen, Germany. Sandra.Mueller@med3.imed.uni-erlangen.de
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Mueller
authors.forename: Birgit
authors.initials: B
authors.lastname: Schaetz
authors.forename: Kathrin
authors.initials: K
authors.lastname: Eismann
authors.forename: Silke
authors.initials: S
authors.lastname: Bergmann
authors.forename: Michael
authors.initials: M
authors.lastname: Bauerle
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmitt-Haendle
authors.forename: Hauke
authors.initials: H
authors.lastname: Walter
authors.forename: Barbara
authors.initials: B
authors.lastname: Schmidt
authors.forename: Klaus
authors.initials: K
authors.lastname: Korn
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.forename: Bernd
authors.initials: B
authors.lastname: Spriewald
authors.forename: Ellen G
authors.initials: EG
authors.lastname: Harrer
authors.forename: Thomas
authors.initials: T
authors.lastname: Harrer
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015331:Cohort Studies; D024882:Drug Resistance, Viral; D018984:Epitopes, T-Lymphocyte; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008969:Molecular Sequence Data; D012641:Selection, Genetic; D019562:Viral Load
chemical_list: D018984:Epitopes, T-Lymphocyte; D017320:HIV Protease Inhibitors; D015395:Histocompatibility Antigens Class I; D016333:HIV Protease