<scp>CTL</scp> recognition of <scp>HIV</scp>‐1‐infected cells via cross‐recognition of multiple overlapping peptides from a single 11‐mer <scp>P</scp>ol sequence

Hashimoto, Masao; Akahoshi, Tomohiro; Murakoshi, Hayato; Ishizuka, Naoki; Oka, Shinichi; Takiguchi, Masafumi

doi:10.1002/eji.201242483

Cited by 6 publications

(7 citation statements)

References 31 publications

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“…Previous studies indicated that HLA-B57-restricted KI8 and KF10 or HLA-B35-restricted VY8 and RY11 superimposed epitopes induce independent CTL responses (7,10), but that HLA-B54-restricted FV9 and FP10 superimposed epitopes elicit mainly cross-reactive CTLs in HIV-1-infected patients (8). Although the detailed mechanisms remain unclear, these studies suggest that different lengths or conformations of a peptide may determine the nature of the CTL response.…”

Section: Discussionmentioning

confidence: 98%

“…Of note, two epitopes in which a shorter one is embedded within a longer one are defined as superimposed epitopes, and they have been shown to be presented by the same MHCI molecule (4)(5)(6). A number of studies have reported CTL responses against such superimposed peptides in the context of an HIV-1 infection (7)(8)(9)(10). For instance, these responses include CTLs specific for HLA-B57-restricted p24 Gag-derived peptides, for example, KI8 (residues 162-169, KAFSPEVI) and KF11 (residues 162-172, KAFSPEVIPMF), as well as for HLA-B*35:01-restricted Nef-derived peptides, for example, VY8 (residues 74-81, VPLRPMTY) and RY11 (residues 71-81, RPQVPLRPMTY).…”

Section: Ytotoxic Cd8mentioning

confidence: 99%

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Superimposed Epitopes Restricted by the Same HLA Molecule Drive Distinct HIV-Specific CD8+ T Cell Repertoires

Sun

Fujiwara

Shi

et al. 2014

The Journal of Immunology

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Superimposed epitopes, in which a shorter epitope is embedded within a longer one, can be presented by the same HLA class I molecule. CD8+ CTL responses against such epitopes and the contribution of this phenomenon to immune control are poorly characterized. In this study, we examined HLA-A*24:02–restricted CTLs specific for the superimposed HIV Nef epitopes RYPLTFGWCF (RF10) and RYPLTFGW (RW8). Unexpectedly, RF10-specific and RW8-specific CTLs from HIV-1–infected HLA-A*24:02+ individuals had no overlapping Ag reactivity or clonotypic compositions. Single-cell TCR sequence analyses demonstrated that RF10-specific T cells had a more diverse TCR repertoire than did RW8-specific T cells. Furthermore, RF10-specific CTLs presented a higher Ag sensitivity and HIV suppressive capacity compared with RW8-specific CTLs. Crystallographic analyses revealed important structural differences between RF10– and RW8–HLA-A*24:02 complexes as well, with featured and featureless conformations, respectively, providing an explanation for the induction of distinct T cell responses against these epitopes. The present study shows that a single viral sequence containing superimposed epitopes restricted by the same HLA molecule could elicit distinct CD8+ T cell responses, therefore enhancing the control of HIV replication. This study also showed that a featured epitope (e.g., RF10) could drive the induction of T cells with high TCR diversity and affinity.

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Section: Discussionmentioning

confidence: 98%

Section: Ytotoxic Cd8mentioning

confidence: 99%

Superimposed Epitopes Restricted by the Same HLA Molecule Drive Distinct HIV-Specific CD8+ T Cell Repertoires

Sun

Fujiwara

Shi

et al. 2014

The Journal of Immunology

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“…However, this may be an underestimate. The frequency may be higher if HIV-1-specific T cells are measured by tetramers, since the ELISpot assay is less sensitive than the tetramer-binding one (47). The frequency of HIV-1-specific T cells is much lower in ART patients than in treatmentnaïve ones (48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Broad Recognition of Circulating HIV-1 by HIV-1-Specific Cytotoxic T-Lymphocytes with Strong Ability to Suppress HIV-1 Replication

Murakoshi

Kuse

Akahoshi

et al. 2019

J Virol

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HIV-1-specific cytotoxic T-lymphocytes (CTLs) with strong abilities to suppress HIV-1 replication and recognize most circulating HIV-1 strains are candidates for effector T cells for cure treatment and prophylactic AIDS vaccine. Previous studies demonstrated that the existence of CTLs specific for 11 epitopes was significantly associated with good clinical outcomes in Japan, although CTLs specific for one of these epitopes select for escape mutations. However, it remains unknown whether the CTLs specific for the remaining 10 epitopes suppress HIV-1 replication in vitro and recognize circulating HIV-1. Here, we investigated the abilities of these CTLs to suppress HIV-1 replication and to recognize variants in circulating HIV-1. CTL clones specific for 10 epitopes had strong abilities to suppress HIV-1 replication in vitro. The ex vivo and in vitro analyses of T-cell responses to variant epitope peptides showed that the T cells specific for 10 epitopes recognized mutant peptides which are detected in 84.1% to 98.8% of the circulating HIV-1 strains found in HIV-1-infected Japanese individuals. In addition, the T cells specific for 5 epitopes well recognized target cells infected with 7 mutant viruses that had been detected in >5% of tested individuals. Taken together, these results suggest that CTLs specific for the 10 epitopes effectively suppress HIV-1 replication and broadly recognize the circulating HIV-1 strains in the HIV-1-infected individuals. This study suggests the use of these T cells in clinical trials. IMPORTANCE In recent T-cell AIDS vaccine trials, the vaccines did not prevent HIV-1 infection, although HIV-1-specific T cells were induced in the vaccinated individuals, suggesting that the T cells have a weak ability to suppress HIV-1 replication and fail to recognize circulating HIV-1. We previously demonstrated that the T-cell responses to 10 epitopes were significantly associated with good clinical outcome. However, there is no direct evidence that these T cells have strong abilities to suppress HIV-1 replication and recognize circulating HIV-1. Here, we demonstrated that the T cells specific for the 10 epitopes had strong abilities to suppress HIV-1 replication in vitro. Moreover, the T cells cross-recognized most of the circulating HIV-1 in HIV-1-infected individuals. This study suggests the use of T cells specific for these 10 epitopes in clinical trials of T-cell vaccines as a cure treatment.

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“…HLA-B*40:06-PolGA9 or -PolLA9 peptide tetrameric complexes (tetramers) and HLA-B*40:02-PolGI8, HLA-A*24:02-NefRF10 or -GagKW9, HLA-B*54:01-PolFP10, -PolFV9, or -PolFV11, HLA-A*11:01-NefQK10 complexes were generated as previously described ( 33 , 37 , 38 , 45 ). PBMCs or the bulk T cells were stained with phycoerythrin-conjugated epitope-specific tetramers at 37°C for 30 min.…”

Section: Methodsmentioning

confidence: 99%

Epitope-dependent effect of long-term cART on maintenance and recovery of HIV-1-specific CD8 ⁺ T cells

Kuse,

Gatanaga,

Zhang

et al. 2023

J Virol

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The frequency of HIV-1-specific T cells is reduced and their functional ability remains impaired in people living with HIV-1 (PLWH) under combined antiretroviral therapy (cART). However, no studies have yet reported on T-cell responses to large numbers of well-characterized HIV-1 epitopes before and under cART within the same individuals. Therefore, how cART affects the maintenance of HIV-1-specific CD8 + T cells and which HIV-1-specific CD8 + T cells would be useful for curative treatment remain unclear. We investigated T-cell responses to 63 HIV-1 epitopes at pre-cART and under cART in 90 PLWH who received long-term cART. The frequency of T-cell responses to HIV-1 epitopes under long-term cART varied from 0% to 100%, indicating an epitope-dependent effect of long-term cART on HIV-1-specific CD8 + T cells. The magnitude of the responses under cART was 26.2% of that at pre-cART. The frequency of T-cell responses to protective epitopes under cART was higher than that to non-protective ones. T-cell responses to HIV-1 epitopes were detected at pre-cART in most non-AIDS HIV patients, whereas they were not detectable at pre-cART in half of the AIDS patients. Long-term cART enhanced the ability of HIV-1-specific T cells to proliferate in vitro in non-AIDS HIV patients, while it restored this ability of the T cells in AIDS patients. This study demonstrated that CD8 + T cells specific for large numbers of HIV-1 epitopes were maintained in an epitope-dependent fashion under long-term cART and implied that some HIV-1-specific T cells are still candidates as effector cells for curative treatment. IMPORTANCE HIV-1-specific CD8 + T cells are anticipated to become effector cells for curative treatment using the “shock and kill” approach in people living with HIV-1 (PLWH) under combined antiretroviral therapy (cART). Previous studies demonstrated that the frequency of HIV-1-specific CD8 + T cells is reduced under cART and their functional ability remains impaired. These studies analyzed T-cell responses to a small number of HIV-1 epitopes or overlapping HIV-1 peptides. Therefore, the features of CD8 + T cells specific for HIV-1 epitopes under cART remain only partially clarified. Here, we analyzed CD8 + T cells specific for 63 well-characterized epitopes in 90 PLWH. We demonstrated that CD8 + T cells specific for large numbers of HIV-1 epitopes were maintained in an epitope-dependent fashion under long-term cART and that long-term cART enhanced or restored the ability of HIV-1-specific T cells to proliferate in vitro . This study implies that some HIV-1-specific T cells would be useful as effector cells for curative treatment.

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CTL recognition of HIV‐1‐infected cells via cross‐recognition of multiple overlapping peptides from a single 11‐mer Pol sequence

Cited by 6 publications

References 31 publications

Superimposed Epitopes Restricted by the Same HLA Molecule Drive Distinct HIV-Specific CD8+ T Cell Repertoires

Superimposed Epitopes Restricted by the Same HLA Molecule Drive Distinct HIV-Specific CD8+ T Cell Repertoires

Broad Recognition of Circulating HIV-1 by HIV-1-Specific Cytotoxic T-Lymphocytes with Strong Ability to Suppress HIV-1 Replication

Epitope-dependent effect of long-term cART on maintenance and recovery of HIV-1-specific CD8 ⁺ T cells

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CTL recognition of HIV‐1‐infected cells via cross‐recognition of multiple overlapping peptides from a single 11‐mer Pol sequence

Cited by 6 publications

References 31 publications

Superimposed Epitopes Restricted by the Same HLA Molecule Drive Distinct HIV-Specific CD8+ T Cell Repertoires

Superimposed Epitopes Restricted by the Same HLA Molecule Drive Distinct HIV-Specific CD8+ T Cell Repertoires

Broad Recognition of Circulating HIV-1 by HIV-1-Specific Cytotoxic T-Lymphocytes with Strong Ability to Suppress HIV-1 Replication

Epitope-dependent effect of long-term cART on maintenance and recovery of HIV-1-specific CD8 + T cells

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Product

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Epitope-dependent effect of long-term cART on maintenance and recovery of HIV-1-specific CD8 ⁺ T cells