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. 2015 Jul;89(14):7363-72.
doi: 10.1128/JVI.00974-15. Epub 2015 May 13.

Different Effects of Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutations on Cytotoxic T Lymphocyte Recognition between HIV-1 Subtype B and Subtype A/E Infections

Nozomi Kuse  1 , Mohammad Arif Rahman  1 , Hayato Murakoshi  1 , Giang Van Tran  1 , Takayuki Chikata  1 , Madoka Koyanagi  1 , Kinh Van Nguyen  2 , Hiroyuki Gatanaga  3 , Shinichi Oka  3 , Masafumi Takiguchi  4
Affiliations

Different Effects of Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutations on Cytotoxic T Lymphocyte Recognition between HIV-1 Subtype B and Subtype A/E Infections

Nozomi Kuse et al. J Virol. 2015 Jul.

Abstract

The effect of antiretroviral drug resistance mutations on cytotoxic T lymphocyte (CTL) recognition has been analyzed in HIV-1 subtype B infections, but it remains unclear in infections by other HIV-1 subtypes that are epidemic in countries where antiretroviral drugs are not effectively used. We investigated the effect of nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI)-resistance mutations (Y181C, Y181I, and Y181V) on epitope recognition by CTLs specific for 3 different HIV-1 epitopes (HLA-A*02:01-restricted IV10, HLA-B*35:01-restricted NY9, and HLA-C*12:02-restricted KY9) in subtype B and subtype A/E infections and the accumulation of these mutations in treatment-naive Japanese and Vietnamese. These NNRTI-resistance mutations critically affected NY9-specific and KY9-specific T cell responses in the subtype B infections, whereas they showed a different effect on IV10-specific T cell responses among the subtype B-infected individuals. These mutations affected IV10-specific T cell responses but weakly affected NY9-specific T cell responses in the subtype A/E infections. The substitution at position 3 of NY9 epitope which was found in the subtype A/E virus differently influenced the peptide binding to HLA-B*35:01, suggesting that the differences in peptide binding may result in the differences in T cell recognition between the subtype B virus and A/E virus infections. The Y181C mutation was found to be accumulating in treatment-naive Vietnamese infected with the subtype A/E virus. The present study demonstrated different effects of NNRTI-resistance RT181 mutations on CTL responses between the 2 subtype infections. The Y181C mutation may influence HIV-1 control by the CTLs in Vietnam, since this mutation has been accumulating in treatment-naive Vietnamese.

Importance: Antiretroviral therapy leads to the emergence of drug-resistant HIV-1, resulting in virological and clinical failures. Though HIV-1-specific CTLs play a critical role in HIV-1 infection, some of drug resistance mutations located in CTL epitopes are known to affect HIV-1-specific CTL responses. Nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistance RT181 mutations are frequently observed in patients treated with NNRTIs. Such drug resistance mutations may have an influence on immune control by HIV-1-specific CTLs, especially in countries where antiretroviral drugs are not effectively used. We here investigated the effect of three NNRTI-resistance RT181 mutations on immune responses by HIV-1-specific CTLs and the recent accumulation of these mutations in treatment-naive Vietnamese infected with HIV-1 subtype A/E virus. RT181 mutations affected CTL recognition in both subtype A/E and B infections, while the RT Y181C mutation has been accumulating in treatment-naive Vietnamese. The results suggest that the Y181C mutation may influence HIV-1 control by CTLs in Vietnam.

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Figures

FIG 1
FIG 1
Recognition of RT181 mutations by HLA-A*02:01-restricted IV10-specific CTLs. (A) Ex vivo CD8+ T cell responses to IV10 (WT) or the mutant peptides in HLA-A*02:01+ individuals infected with the subtype B virus or the subtype A/E virus. CD8+ T cell responses to IV10 or the mutant peptides by PBMCs in 7 HIV-1-infected individuals were analyzed by performing the ELISPOT assay using a 100 nM concentration of peptides. (B) Relative cytotoxic activity of HLA-A*02:01-restricted IV10-specific bulk T cells toward C1R-A*0201 cells prepulsed with the peptides. It was measured by performing the 51Cr release assay. (C) Binding of the IV10 and mutant peptides to HLA-A*02:01. Binding ability was measured by performing the HLA class I stabilization assay using RMA-S-A*0201 cells. (D) Relative cytotoxic activity of IV10-specific bulk T cells against 721.221-CD4-HLA-A*0201 cells infected with the wild-type (NL-432) or mutant viruses. The frequencies of p24 antigen-positive cells among 721.221-CD4-HLA-A*0201 cells infected with NL-432, NL-432-Y181C, NL-432-Y181V, and NL-432-Y181I were 62%, 44%, 51%, and 41%, respectively, for KI-634; 59%, 59%, 53%, and 41%, respectively, for KI-775; and 63%, 61%, 63%, and 60%, respectively, for KI-837. All data are shown as the means and ± standard deviations (SD) of the results of triplicate assays. Statistical analysis was performed by using the t test. *, P < 0.05; **, P < 0.01 (as indicated by the brackets).
FIG 2
FIG 2
Recognition of RT181 mutations by HLA-C*12:02-restricted KY9-specific CTLs. (A) Ex vivo CD8+ T cell responses to KY9 (WT) or the mutant peptides in HLA-C*12:02+ individuals infected with subtype B virus. CD8+ T cell responses to KY9 or the mutant peptides by PBMCs from 2 HIV-1-infected individuals were analyzed by performing the ELISPOT assay using a 100 nM concentration of the peptides. (B) Relative cytotoxic activity of HLA-C*12:02-restricted KY9-specific CTL clones toward C1R-C*1202 cells prepulsed with KY9 or the mutant peptides. (C) Binding of the KY9 and mutant peptides to HLA-C*12:02. Binding ability was measured by performing the HLA class I stabilization assay using RMA-S-C*1202 cells. (D) Relative cytotoxic activity of KY9-specific CTL clones against 721.221-CD4-HLA-C*1202 cells infected with the wild-type (NL-432) or mutant viruses. The frequencies of p24 antigen-positive cells among 721.221-CD4-HLA-C*1202 cells infected with NL-432, NL-432-Y181C, NL-432-Y181V, and NL-432-Y181I were 47%, 44%, 42%, and 54%, respectively. All data are shown as the means and ± SD of the results of triplicate assays. Statistical analysis was performed by using the t test. *, P < 0.05; **, P < 0.01 (as indicated by the brackets).
FIG 3
FIG 3
Effect of RT181 mutations on HLA-B*35:01-restricted NY9-specific CTL recognition in subtype B infections. (A) Ex vivo CD8+ T cell responses to NY9 (WT) or the mutant peptides in HLA-B*35:01+ individuals infected with subtype B virus. CD8+ T cell responses to NY9 or the mutant peptides in PBMCs from 3 HIV-1 subtype B-infected individuals were analyzed by performing the ELISPOT assay using a 100 nM concentration of the peptides. (B) Relative cytotoxic activity of HLA-B*35:01-restricted NY9-specific CTL clones toward C1R-B*3501 cells prepulsed with WT or the mutant peptides. (C) Binding of the NY9 and mutant peptides to HLA-B*35:01. Binding ability was measured by performing the HLA class I stabilization assay using RMA-S-B*3501 cells. (D) Relative cytotoxic activity of NY9-specific CTL clones against 721.221-CD4-HLA-B*3501 cells infected with the wild-type (NL-432) or mutant viruses. The frequencies of p24 antigen-positive cells among 721.221-CD4-HLA-B*3501 cells infected with NL-432, NL-432-Y181C, NL-432-Y181V, and NL-432-Y181I were 55%, 52%, 49%, and 48%, respectively. All data are shown as the means and ± SD of the results of triplicate assays. Statistical analysis was performed by using the t test. *, P < 0.05; **, P < 0.01 (as indicated by the brackets).
FIG 4
FIG 4
Effect of RT181 mutations on HLA-B*35:01-restricted NY9-3E-specific CTL recognition in subtype A/E infections. (A) Ex vivo CD8+ T cell responses to NY9-3E (WT) or 3 mutant peptides in HLA-B*35:01+ individuals infected with subtype A/E virus. CD8+ T cell responses to NY9-3E or 3 mutant peptides in PBMCs from 3 HIV-1-infected individuals were analyzed by performing the ELISPOT assay using a 100 nM concentration of the peptides. (B) Relative cytotoxic activity of HLA-B*35:01-restricted NY9-3E-specific bulk T cells toward C1R-B*3501 cells prepulsed with WT or the mutant peptides. (C) Binding of the NY9-3E and mutant peptides to HLA-B*35:01. Binding ability was measured by performing the HLA class I stabilization assay using RMA-S-B*3501 cells. (D) Relative cytotoxic activity of NY9-3E-specific bulk T cells against 721.221-CD4-HLA-B*3501 cells infected with the wild-type (NL-432-NY9-3E) or mutant viruses. The frequencies of p24 antigen-positive cells among 721.221-CD4-HLA-B*3501 cells infected with NL-432-NY9-3E, NL-432-NY9-3E-Y181C, NL-432-NY9-3E-Y181V, and NL-432-NY9-3E-Y181I were 46%, 49%, 52%, and 48%, respectively, for KI-667 and 60%, 58%, 59%, and 58%, respectively, for KI-805. All data in this figure are shown as the means and ± SD of the results of triplicate assays. Statistical analysis was performed by using the t test. *, P < 0.05; **, P < 0.01 (as indicated by the brackets).
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