Patterns of Immunodominance in HIV-1–specific Cytotoxic T Lymphocyte Responses in Two Human Histocompatibility Leukocyte Antigens (HLA)-identical Siblings with HLA-A*0201 Are Influenced by Epitope Mutation

Goulder, Philip; Sewell, Andrew K.; Lalloo, David G.; Price, David A.; Whelan, Joseph A.; Evans, John W.; Taylor, Graham P.; Luzzi, Graz; Giangrande, Paul; Phillips, Rodney E.; McMichael, Andrew J.

doi:10.1084/jem.185.8.1423

Cited by 172 publications

(136 citation statements)

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“…Furthermore, the pattern of CTL immunodominance may be influenced by epitope mutations, as shown in human immunodeficiency virus infection. 74 Importantly, the CD8 ϩ cytolytic T-cell response in recovered subjects was not significantly different from the uninfected controls in whom CTL response to HCV-derived peptides has been reported. 7 Along this line, the frequent response to another HLA-A2 restricted CTL epitope within the NS3 region (NS3 1073) in all 3 groups, including healthy seronegative controls, suggested that it may reflect a crossreactive response to an unrelated antigen as well as a response to HCV when analyzed using bulk peptide stimulation.…”

Section: Discussionmentioning

confidence: 95%

Differential CD4+ and CD8+ T-cell responsiveness in hepatitis C virus infection

2001

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This study was performed to compare the vigor and phenotype of virus-specific CD4 ؉ and CD8 ؉ T-cell responses in patients with different virologic and clinical outcomes after hepatitis C virus (HCV) infection. The results show that a vigorous and multispecific CD4 ؉ proliferative T-cell response is maintained indefinitely after recovery from HCV infection whereas it is weak and focused in persistently infected patients. In contrast, the HCV-specific CD8 ؉ T-cell response was quantitatively low in both groups despite the use of sensitive direct ex vivo intracellular interferon gamma (IFN-␥) staining. Furthermore, although HCV-specific cytolytic CD8 ؉ memory T cells were undetectable ex vivo, they were readily expanded from the peripheral blood of chronically HCV-infected patients but not from recovered subjects after in vitro stimulation, suggesting that ongoing viremia is required to maintain the HCV-specific memory CD8 ؉ T-cell response. HCV-specific CD8 ؉ T cells displayed a type 1 cytokine profile characterized by production of IFN-␥ despite persistent HCV viremia. The paradoxical observation that HCV-specific CD4 ؉ T cells survive and CD8 ؉ T cells are lost after viral clearance while the opposite occurs when HCV persists suggests the existence of differential requirements for the maintenance of CD4 ؉ and CD8 ؉ T-cell memory during HCV infection. Furthermore, the relative rarity of circulating CD8 ؉ effector T cells in chronically infected patients may explain the chronic insidious nature of the liver inflammation and also why they fail to eliminate the virus. (HEPATOLOGY 2001;33:267-276.)Hepatitis C virus (HCV) is a parenterally transmitted hepatotropic RNA virus that causes acute and chronic hepatitis. 1,2 While acute infection is generally subclinical, and therefore difficult to identify, chronic infection occurs in the majority of cases, and this can be associated with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. 3,4 The role of CD4 ϩ and CD8 ϩ T cells in HCV clearance or disease pathogenesis is not well understood. Certainly, persistent infection occurs despite the presence of virus-specific CD4 ϩ and CD8 ϩ T cells in the liver and the peripheral blood, suggesting that these responses are ineffective in most patients. [5][6][7][8][9][10][11][12] The CD8 ϩ T-cell response to HCV may be only partially successful in virus control because it is quantitatively inadequate, [13][14][15][16][17] and it may also select for immune escape variants that further contribute to viral persistence. 13,[18][19][20] The role of CD8 ϩ T cells in this infection is most clearly illustrated, perhaps, in experimentally infected chimpanzees where a multispecific intrahepatic HCV-specific CD8 ϩ T-cell response during the early phase of infection was associated with subsequent HCV clearance while a more narrowly focused and delayed response was associated with persistent infection. 21 In contrast to these results, however, the relationship between the HCV-specific CD8 ϩ T-cell response and the outcome of infection...

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Section: Discussionmentioning

confidence: 95%

Differential CD4+ and CD8+ T-cell responsiveness in hepatitis C virus infection

2001

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“…Hepatitis B virus core peptide was purchased from NeoMPS Inc. (San Diego, CA). The PS-SCL (free N terminus and amidated C terminus) consists of 180 mixtures in an OX 8 …”

Section: Library and Peptide Synthesismentioning

confidence: 99%

“…About 70% of chronically HIV-infected, HLA-A2-positive individuals have circulating CTL that recognize the Gag p17-derived epitope SLYNTVATL (SL9) [8,9]. Although the in vivo effectiveness of SL9-specific CTL has been questioned [8][9][10][11][12], there may at least be a partial benefit from these responses.…”

Section: Introductionmentioning

confidence: 99%

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Discovery and characterization of highly immunogenic and broadly recognized mimics of the HIV‐1 CTL epitope Gag_77–85

et al. 2005

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Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) play an important role in HIV infection. Given the viral genetic diversity, the selection of suitable antigens and epitope variants will be important in the design of an effective vaccine. We have previously shown that combinatorial libraries are useful tools to identify epitope mimics as well as potentially cross-reactive natural sequences in protein databases. We have applied this approach to the HIV Gag p17-derived epitope SL9 (SLYNTVATL) to identify broadly recognized SL9 mimics and to assess the cross-recognition of naturally occurring SL9 variants. Nine nonapeptides were identified that were up to one order of magnitude more effective than SL9 in stimulating CTL responses in PBMC from HIVinfected subjects. Using transgenic mice, we demonstrate that a number of these epitope mimics were able to generate de novo T cell responses that cross-reacted with the original SL9 sequence. Particularly, mimics with changes at the relatively conserved Fpocket anchor residue were frequently cross-recognized. This approach may lead to vaccine candidates with higher in vivo immunogenicity and increased potential for cross-recognition of naturally occurring SL9 variants.

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“…As one of the more referenced peptides found in literature, FLPSDFF-PSV is known for high affinity binding to A*0201 [46][47][48] as well as for inducing potent CTL responses [49] . Additional controls were the peptides SLYNTVATL and ILKEPVHGV, two other well-studied HIV-derived CTL epitopes [50][51][52] . According to our FP-based classification system, wildtype peptides wt1131 and wt1169 were found to be of high and medium affinity, respectively, matching with the high cytolytic activity level of these CTL clones ( Figure 4B and C).…”

Section: Impact Of Variant Peptides On Mhc Class ⅰ Bindingmentioning

confidence: 99%

Natural epitope variants of the hepatitis C virus impair cytotoxic T lymphocyte activity

Wang

Buchli

Schiller

et al. 2010

WJG

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AIM:To understand how interactions between hepatitis C virus (HCV) and the host's immune system might lead to viral persistence or effective elimination of HCV. METHODS:Nucleotides 3519-3935 of the non-structural 3 (NS3) region were amplified by using reverse transcription polymerase chain reaction (PCR). PCR products of the HCV NS3 regions were integrated into a PCR ® T7TOPO ® TA vector and then sequenced in both directions using an automated DNA sequencer. Relative major histocompatibility complex binding levels of wild-type and variant peptides were performed by fluorescence polarization-based peptide competition assays. Peptides with wild type and variant sequences of NS3 were synthesized locally using F-moc chemistry and purified by high-performance liquid chromatography. Specific cytotoxic T lymphocytes (CTLs) clones toward HCV NS3 wild-type peptides were generated through limiting dilution cloning. The CTL clones specifically recognizing HCV NS3 wild-type peptides were tested by tetramer staining and flow cytometry. Cytolytic activity of CTL clones was measured using target cells labeled with the fluorescence enhancing ligand, DELFIA EuTDA. RESULTS:The pattern of natural variants within three human leukocyte antigen (HLA)-A2-restricted NS3 epitopes has been examined in one patient with chronic HCV infection at 12, 28 and 63 mo post-infection. Results obtained may provide convincing evidence of immune selection pressure for all epitopes investigated. Statistical analysis of the extensive sequence variation found within these NS3 epitopes favors a Darwinian selection model of variant viruses. Mutations within the epitopes coincided with the decline of CTL responses, and peptide-binding studies suggested a significant impact of the mutation on T cell recognition rather than peptide presentation by HLA molecules. While most variants were either not recognized or elicited low responses, such could antagonize CTL responses to target cells pulsed with wild-type peptides. CONCLUSION:Cross-recognition of CTL epitopes from wild-type and naturally-occurring HCV variants may lead to impaired immune responses and ultimately contribute to viral persistence.

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Patterns of Immunodominance in HIV-1–specific Cytotoxic T Lymphocyte Responses in Two Human Histocompatibility Leukocyte Antigens (HLA)-identical Siblings with HLA-A*0201 Are Influenced by Epitope Mutation

Cited by 172 publications

References 43 publications

Differential CD4+ and CD8+ T-cell responsiveness in hepatitis C virus infection

Differential CD4+ and CD8+ T-cell responsiveness in hepatitis C virus infection

Discovery and characterization of highly immunogenic and broadly recognized mimics of the HIV‐1 CTL epitope Gag_77–85

Natural epitope variants of the hepatitis C virus impair cytotoxic T lymphocyte activity

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Patterns of Immunodominance in HIV-1–specific Cytotoxic T Lymphocyte Responses in Two Human Histocompatibility Leukocyte Antigens (HLA)-identical Siblings with HLA-A*0201 Are Influenced by Epitope Mutation

Cited by 172 publications

References 43 publications

Differential CD4+ and CD8+ T-cell responsiveness in hepatitis C virus infection

Differential CD4+ and CD8+ T-cell responsiveness in hepatitis C virus infection

Discovery and characterization of highly immunogenic and broadly recognized mimics of the HIV‐1 CTL epitope Gag77–85

Natural epitope variants of the hepatitis C virus impair cytotoxic T lymphocyte activity

Contact Info

Product

Resources

About

Discovery and characterization of highly immunogenic and broadly recognized mimics of the HIV‐1 CTL epitope Gag_77–85