Dual selection pressure by drugs and HLA class I-restricted immune responses on human immunodeficiency virus type 1 protease.
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.
Mueller
Sandra M
SM
Immunodeficiency Center of the Department of Medicine III, University Hospital Erlangen, Krankenhausstrasse 12, 91054 Erlangen, Germany. Sandra.Mueller@med3.imed.uni-erlangen.de
Schaetz
Birgit
B
Eismann
Kathrin
K
Bergmann
Silke
S
Bauerle
Michael
M
Schmitt-Haendle
Matthias
M
Walter
Hauke
H
Schmidt
Barbara
B
Korn
Klaus
K
Sticht
Heinrich
H
Spriewald
Bernd
B
Harrer
Ellen G
EG
Harrer
Thomas
T
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
D018984:Epitopes, T-Lymphocyte; D017320:HIV Protease Inhibitors; D015395:Histocompatibility Antigens Class I; D016333:HIV Protease