Influence of major HIV-1 protease inhibitor resistance mutations on CTL recognition.
BACKGROUND
HIV-1 protease is subjected to dual selection pressure exerted by protease inhibitors (PIs) and cytotoxic T lymphocytes (CTL). Recently, we identified KMIGGIGGF (KF9) as a HLA-B*1501-restricted CTL epitope, including several major PI resistance mutations (M46I/L, I47A/V, G48V, I50V). To assess potential interactions between KF9-specific CTL and emergence of these important resistance mutations, we studied CTL recognition of the mutations and analyzed protease sequences in an HLA-I–typed patient cohort.


METHODS
CTL recognition of KF9 and resistance mutations in KF9 were studied in 38 HLA-B*1501-positive HIV-1–infected patients using variant KF9 peptides in interferon-g enzyme-linked immunospot assays. Protease sequences were analyzed in 302 HLA-I–typed HIV-1–infected patients.


RESULTS
G48V abolished KF9 recognition by CTL in all patients. Furthermore, M46I, I47A, and I50V could impair or abolish CTL recognition in many patients. In contrast, M46L and I47V showed good CTL recognition in nearly all patients. HIV-1 protease sequence analysis showed no statistical correlation between the occurrence of resistance mutations in KF9 and HLA-B*1501. Viral load in patients failing therapy with KF9 mutations was significantly lower in HLA-B*1501-positive patients in comparison with HLA-B*1501-negative patients.


CONCLUSIONS
PI mutations, G48V, M46I, and I47A, can abrogate CTL recognition, indicating potential interactions between development of drug resistance and CTL response. However, we could not find evidence that development of these PI mutations is influenced by KF9-specific CTL.
Department of Internal Medicine 3, Institute of Clinical Immunology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany. sandra.mueller@uk-erlangen.de
Sandra M
SM
Mueller
Bernd M
BM
Spriewald
Silke
S
Bergmann
Kathrin
K
Eismann
Melanie
M
Leykauf
Klaus
K
Korn
Hauke
H
Walter
Barbara
B
Schmidt
Marie-Luise
ML
Arnold
Ellen G
EG
Harrer
Rolf
R
Kaiser
Finja
F
Schweitzer
Patrick
P
Braun
Stefan
S
Reuter
Hans
H
Jaeger
Eva
E
Wolf
Norbert H
NH
Brockmeyer
Klaus
K
Jansen
Claudia
C
Michalik
Thomas
T
Harrer
D024882:Drug Resistance, Viral; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000821:virology; D016333:HIV Protease / Q000235:genetics / Q000276:immunology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D015235:HLA-B Antigens / Q000276:immunology; D006801:Humans; D020125:Mutation, Missense; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D017320:HIV Protease Inhibitors; D015235:HLA-B Antigens; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1