Analysis of immune selection as a potential cause for the presence of cleavage site mutation 431V in treatment-naive HIV type-1 isolates.
BACKGROUND
HIV type-1 (HIV-1) protease (PR) and cleavage site (CS) mutations accumulate in protease-inhibitor-resistant isolates. HIV-1 CS mutation 431V is the most frequent treatment-associated CS mutation; however, little is known about its origin in treatment-naive HIV-1 isolates. Recently, it has been shown that the CS mutation 431V is located within the human leukocyte antigen (HLA)-B*13-restricted cytotoxic T-lymphocyte (CTL) epitope RQANFLGKI (RI9). Therefore, we investigated whether the presence of CS mutation 431V might additionally be related to immune escape.


METHODS
CTL recognition of RI9 and of RI9 variants carrying the 431V or the 436R mutation was analysed by ELISPOT in nine HLA-B*13-positive HIV-1-infected patients. Treatment-naive HIV-1-infected patients with primary drug-resistant HIV-1 isolates (n=58) or carrying 431V (n=4) were genotyped for HLA class I alleles.


RESULTS
ELISPOT analysis showed different patterns of CTL recognition of RI9. CS mutation 431V could abrogate recognition by RI9-specific CTL in a subgroup of patients. Nevertheless, in our study, the occurrence of 431V in treatment-naive HIV-1 without primary drug resistance could not be explained by HLA-B*13-mediated immune selection. In patients with primary drug-resistant HIV-1 isolates, the frequency of HLA-B*13 was not increased and HLA-B*13 did not correlate with CS mutations 436R or 431V.


CONCLUSIONS
HIV-1 CS mutation 431V can abrogate CTL recognition, indicating interactions between development of drug resistance and the CTL response. However, we could not find evidence that the presence of 431V in treatment-naive HIV-1 isolates with and without primary drug resistance is related to immune selection by HLA-B*13 or other HLA class I alleles.
Verheyen
Jens
J
Institute of Virology, University of Cologne, Germany. jens.verheyen@uk-koeln.de
Schweitzer
Finja
F
Harrer
Ellen G
EG
Knops
Elena
E
Mueller
Sandra M
SM
Däumer
Martin
M
Eismann
Kathrin
K
Bergmann
Silke
S
Spriewald
Bernd M
BM
Kaiser
Rolf
R
Harrer
Thomas
T
D016022:Case-Control Studies; D015331:Cohort Studies; D024921:Drug Resistance, Multiple, Viral; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification; D015235:HLA-B Antigens / Q000276:immunology; D006801:Humans; D009154:Mutation; D011480:Protease Inhibitors / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D011480:Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus