Selection of escape mutant by HLA‐C‐restricted HIV‐1 Pol‐specific cytotoxic T lymphocytes carrying strong ability to suppress HIV‐1 replication

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HLA-B*52:01-C*12:02, which is the most abundant haplotype in Japan, has a protective effect on disease progression in HIV-1-infected Japanese individuals, whereas HLA-B*57 and -B*27 protective alleles are very rare in Japan. A previous study on HLA-associated polymorphisms demonstrated that the number of HLA-B*52:01-associated mutations at four Pol positions was inversely correlated with plasma viral load (pVL) in HLA-B*52:01-negative individuals, suggesting that the transmission of HIV-1 with these mutations could modulate the pVL in the population. However, it remains unknown whether these mutations were selected by HLA-B*52:01-restricted CTLs and also reduced viral fitness. In this study, we identified two HLA-B*52:01-restricted and one HLA-C*12:02-restricted novel cytotoxic T-lymphocyte (CTL) epitopes in Pol. Analysis using CTLs specific for these three epitopes demonstrated that these CTLs failed to recognize mutant epitopes or more weakly recognized cells infected with mutant viruses than wild-type virus, supporting the idea that these mutations were selected by the HLA-B*52:01- or HLA-C*12:02-restricted T cells. We further showed that these mutations reduced viral fitness, although the effect of each mutation was weak. The present study demonstrated that the accumulation of these Pol mutations selected by HLA-B*52:01- or HLA-C*12:02-restricted CTLs impaired viral replication capacity and thus reduced the pVL. The fitness cost imposed by the mutations partially accounted for the effect of the HLA-B*52:01-C*12:02 haplotype on clinical outcome, together with the effect of HLA-B*52:01-restricted CTLs on viral replication, which had been previously demonstrated. IMPORTANCE Numerous population-based studies identified HLA-associated HIV-1 mutations to predict HIV-1 escape mutations from cytotoxic T lymphocytes (CTLs). However, the majority of these HLA-associated mutations have not been identified as CTL escape mutations. Our previous population-based study showed that five HLA-B*52:01-associated mutations at four Pol positions were inversely correlated with the plasma viral load in HLA-B*52:01-negative Japanese individuals. In the present study, we demonstrated that these mutations were indeed selected by CTLs specific for novel B*52:01- and C*12:02-restricted epitopes and that the accumulation of these mutations reduced the viral fitness in vitro. This study elucidated the mechanism by which the accumulation of these CTL escape mutations contributed to the protective effect of the HLA-B*52:01-HLA-C*12:02 haplotype on disease progression in HIV-1-infected Japanese individuals.

Section: Discussionmentioning

confidence: 92%

“…C1R cells expressing HLA-B*52:01 or HLA-C*12:02 and 721.221 cells expressing CD4 molecules as well as HLA-B*52:01 or HLA-C*12:02 were previously generated (36,38,39) and maintained in RPMI medium with 10% fetal calf serum (FCS) and 0.15 mg/ml hygromycin B.…”

Section: Methodsmentioning

confidence: 99%

Accumulation of Pol Mutations Selected by HLA-B52:01-C12:02 Protective Haplotype-Restricted Cytotoxic T Lymphocytes Causes Low Plasma Viral Load Due to Low Viral Fitness of Mutant Viruses

Murakoshi

Koyanagi

Chikata

et al. 2017

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“…The Y181C mutation is selected in patients receiving NVP, etravirine (ETR), and ripivirine (RPV) and reduces susceptibility to these drugs and EFV, whereas Y181I/V mutations are selected by NVP and ETR and cause resistance to these drugs and to RPV (16)(17)(18)(19)(20)(21)(22)(23). These 3 RT181 mutations are located in previously reported epitopes, HLA-A*02:01-restricted IV10 (RT 180 -189), HLA-B*35:01-restricted NY9 (RT 175-183), and HLA-C*12:02-restricted KY9 (RT 173-181), in HIV-1 subtype B (24)(25)(26). We investigated here the effect of the RT181 mutations on epitope recognition by CTLs specific for 3 different epitopes in HIV-1 subtype B and subtype A/E infections and the accumulation of these mutations in treatment-naive Japanese and Vietnamese to clarify the effect of these NNRTI-resistance mutations on immune control of HIV-1.…”

mentioning

confidence: 81%

“…C1R-A*0201, -B*3501, and -C*1202, 721.221-CD4-B*3501 and -C*1202, and RMA-S-B*3501 were previously generated (25)(26)(27)(28)(29). 721.221-CD4-A*0201 and RMA-S-A*0201 were obtained by transfecting 721.221-CD4 cells and RMA-S cells, respectively, with the HLA-A*02:01 gene.…”

Section: Methodsmentioning

confidence: 99%

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

Kuse

Rahman

Murakoshi

et al. 2015

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“…It is well known that some escape mutations affect replication capacity and that HIV-1 containing such mutations reverts to WT in individuals not carrying HLA class I restriction alleles (23,32). We previously showed that the 3R mutation does not affect replication capacity when 2 T cell lines are used in an assay measuring it (46).…”

Section: Figmentioning

confidence: 98%

Selection and Accumulation of an HIV-1 Escape Mutant by Three Types of HIV-1-Specific Cytotoxic T Lymphocytes Recognizing Wild-Type and/or Escape Mutant Epitopes

Akahoshi

Chikata

Tamura

et al. 2012

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It is known that cytotoxic T lymphocytes (CTLs) recognizing HIV-1 escape mutants are elicited in HIV-1-infected individuals, but their role in the control of HIV-1 replication remains unclear. We investigated the antiviral ability of CTLs recognizing the HLA-A‫-20:42ء‬restricted Gag28 -36 (KYKLKHIVW) epitope and/or its escape mutant (KYRLKHIVW) elicited in the early and chronic phases of the infection. Wild-type (WT)-epitope-specific CTLs, as well as cross-reactive CTLs recognizing both WT and K30R (3R) epitopes, which were predominantly elicited at early and/or chronic phases in HLA-A‫20:42ء‬ ؉ individuals infected with the WT virus, suppressed the replication of the WT virus but failed to suppress that of the 3R virus, indicating that the 3R virus was selected by these 2 types of CTLs. On the other hand, cross-reactive and 3R-specific CTLs, which were elicited in those infected with the 3R virus, did not suppress the replication of either WT or 3R virus, indicating that these CTLs did not contribute to the control of 3R virus replication. High accumulation of the 3R mutation was found in a Japanese population recently recruited. The selection and accumulation of this 3R mutation resulted from the antiviral ability of these Gag28-specific CTLs and high prevalence of HLA-A‫20:42ء‬ in a Japanese population. The present study highlighted the mechanisms for the roles of cross-reactive and mutant-epitope-specific CTLs, as well as high accumulation of escape mutants, in an HIV-1-infected population.