Heteroclitic peptides enhance human immunodeficiency virus-specific CD8+ T cell responses

Gladney, Krista H.; Pohling, Julia; Hollett, Natasha A.; Zipperlen, Katrin; Gallant, Maureen; Grant, Michael D.

doi:10.1016/j.vaccine.2012.09.067

Cited by 8 publications

(17 citation statements)

References 54 publications

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“…MHC molecules were diluted in PBS supplemented with 0.5 mg/ml b-g-globulin (Sigma-Aldrich) to a final concentration of 0.75 mM and pipetted into a 96-well microplate. Tracer peptide FLPSDCFPSV (based on FLPSDFFPSV, Hepatitis B virus core protein (18)(19)(20)(21)(22)(23)(24)(25)(26)(27) ) with a fluorescent TAMRA molecule covalently bound to the cysteine residue through a maleimide linkage was used as the competitor peptide (38). This tracer peptide was diluted in PBS/b-g-globulin to a concentration of 6 nM and pipetted into a 96-well microplate.…”

Section: Peptide Binding and Stabilitymentioning

confidence: 99%

“…Anchor substitutions have been introduced successfully within peptides to improve MHC class I binding and to enhance TCR activation (12,(17)(18)(19). Substitutions in the TCR interacting region, however, frequently result in heteroclitic analogs that can lead to hyperstimulation of the CTL, achieving occasionally a more potent immune response compared with the native epitope; far more often, they will cause T cell exhaustion or lead to an abrogated TCR interaction (20)(21)(22).…”

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confidence: 99%

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Altered Peptide Ligands Revisited: Vaccine Design through Chemically Modified HLA-A2–Restricted T Cell Epitopes

Hoppes

Oostvogels

Luimstra

et al. 2014

The Journal of Immunology

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Virus or tumor Ag–derived peptides that are displayed by MHC class I molecules are attractive starting points for vaccine development because they induce strong protective and therapeutic cytotoxic T cell responses. In thus study, we show that the MHC binding and consequent T cell reactivity against several HLA-A*02 restricted epitopes can be further improved through the incorporation of nonproteogenic amino acids at primary and secondary anchor positions. We screened more than 90 nonproteogenic, synthetic amino acids through a range of epitopes and tested more than 3000 chemically enhanced altered peptide ligands (CPLs) for binding affinity to HLA-A*0201. With this approach, we designed CPLs of viral epitopes, of melanoma-associated Ags, and of the minor histocompatibility Ag UTA2-1, which is currently being evaluated for its antileukemic activity in clinical dendritic cell vaccination trials. The crystal structure of one of the CPLs in complex with HLA-A*0201 revealed the molecular interactions likely responsible for improved binding. The best CPLs displayed enhanced affinity for MHC, increasing MHC stability and prolonging recognition by Ag-specific T cells and, most importantly, they induced accelerated expansion of antitumor T cell frequencies in vitro and in vivo as compared with the native epitope. Eventually, we were able to construct a toolbox of preferred nonproteogenic residues with which practically any given HLA-A*02 restricted epitope can be readily optimized. These CPLs could improve the therapeutic outcome of vaccination strategies or can be used for ex vivo enrichment and faster expansion of Ag-specific T cells for transfer into patients.

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Section: Peptide Binding and Stabilitymentioning

confidence: 99%

mentioning

confidence: 99%

Altered Peptide Ligands Revisited: Vaccine Design through Chemically Modified HLA-A2–Restricted T Cell Epitopes

Hoppes

Oostvogels

Luimstra

et al. 2014

The Journal of Immunology

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“…If the heteroclitic peptides stimulate a different subset of CD8 + T cells than the reference peptides, we would expect reference and heteroclitic peptides together to produce an additive response in ELIspot assays. However, when we previously tested this possibility, adding reference and heteroclitic peptides together did not increase responses above those stimulated by the heteroclitic peptide alone (10).…”

Section: Fig 3 (A)mentioning

confidence: 93%

“…We previously showed that conservative or semiconservative aa variation at positions 3, 5, and 7, sites within HLAclass I-restricted peptide epitopes predicted to interact with the TCR, can generate heteroclitic HIV peptides that trigger stronger cytokine responses by HIV-specific CD8 + T cells cross-reactive with the reference peptide (10). However, we did not test the effects of these heteroclitic peptides on other important HIV-specific CD8 + T cell functions such as proliferation and differentiation.…”

Section: Introductionmentioning

confidence: 90%

“…Subjects with CD8 + T cell responses against reference HIV peptides were identified as previously described (10). Four consensus clade B, immunodominant, HLA-A2-restricted, and optimally defined HIV peptide epitopes commonly recognized by HIV-infected subjects in our cohort were chosen as reference peptides and a series of six sequence variants were synthesized per peptide.…”

Section: Peptidesmentioning

confidence: 99%

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Heteroclitic Peptides Increase Proliferation and Reduce Evidence of Human Immunodeficiency Virus-Specific CD8⁺T Cell Dysfunction

2015

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Human immunodeficiency virus (HIV)-specific CD8(+) T cell dysfunction parallels disease progression; therefore, restoring potent HIV-specific CD8(+) T cell responses is a key therapeutic goal. Certain CD8(+) T cell peptide epitope variants, termed heteroclitic, enhance cytokine production by the HIV-specific CD8(+) T cells of some individuals. In this study, we investigated whether heteroclitic peptides that enhance cytokine production by HIV-specific CD8(+) T cells also reduce functional and phenotypic evidence of HIV-specific CD8(+) T cell exhaustion in those instances. Twenty-four variant peptides of human histocompatibility-linked leukocyte antigen (HLA)-A2-restricted reference HIV peptide epitopes designated as A2-7; Nef 83→91, A2-8; Nef 135→143, A2-Gag; Gag 77→85 and A2-9; Gag 433→440 were synthesized with conservative and semiconservative amino acid substitutions at positions 3, 5, and 7 or 3, 5, and 8 of Gag 433→440. Variants that enhanced interferon-gamma (IFN-γ) and/or interleukin-2 (IL-2) production in enzyme-linked immunospot assays (29 cases overall) were subsequently tested by 7-day in vitro peptide stimulation for their effects on HIV-specific CD8(+) T cell proliferation and programmed death-1 (PD-1) expression. Heteroclitic variants enhanced HIV-specific CD8(+) T cell proliferation by >20% in 13/29 cases tested, reduced PD-1 expression on proliferating cells by 15-50% in 10 cases, and reduced PD-1 expression on proliferating cells by >50% in 3 cases. In five cases, the same heteroclitic peptide increased proliferation by >20% and reduced PD-1 expression by >15%. These data demonstrate that heteroclitic peptides can alter the magnitude and character of HIV-specific CD8(+) cell responses relative to reference peptides and may have a unique immunotherapeutic value in therapeutic vaccines.

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The bright side of chemistry: Exploring synthetic peptide‐based anticancer vaccines

D'Aniello,

Del Bene,

Mottola

et al. 2024

Journal of Peptide Science

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The present review focuses on synthetic peptide‐based vaccine strategies in the context of anticancer intervention, paying attention to critical aspects such as peptide epitope selection, adjuvant integration, and nuanced classification of synthetic peptide cancer vaccines. Within this discussion, we delve into the diverse array of synthetic peptide‐based anticancer vaccines, each derived from tumor‐associated antigens (TAAs), including melanoma antigen recognized by T cells 1 (Melan‐A or MART‐1), mucin 1 (MUC1), human epidermal growth factor receptor 2 (HER‐2), tumor protein 53 (p53), human telomerase reverse transcriptase (hTERT), survivin, folate receptor (FR), cancer‐testis antigen 1 (NY‐ESO‐1), and prostate‐specific antigen (PSA). We also describe the synthetic peptide‐based vaccines developed for cancers triggered by oncovirus, such as human papillomavirus (HPV), and hepatitis C virus (HCV). Additionally, the potential synergy of peptide‐based vaccines with common therapeutics in cancer was considered. The last part of our discussion deals with the realm of the peptide‐based vaccines delivery, highlighting its role in translating the most promising candidates into effective clinical strategies. Although this discussion does not cover all the ongoing peptide vaccine investigations, it aims at offering valuable insights into the chemical modifications and the structural complexities of anticancer peptide‐based vaccines.

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Heteroclitic peptides enhance human immunodeficiency virus-specific CD8+ T cell responses

Cited by 8 publications

References 54 publications

Altered Peptide Ligands Revisited: Vaccine Design through Chemically Modified HLA-A2–Restricted T Cell Epitopes

Altered Peptide Ligands Revisited: Vaccine Design through Chemically Modified HLA-A2–Restricted T Cell Epitopes

Heteroclitic Peptides Increase Proliferation and Reduce Evidence of Human Immunodeficiency Virus-Specific CD8⁺T Cell Dysfunction

The bright side of chemistry: Exploring synthetic peptide‐based anticancer vaccines

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Heteroclitic peptides enhance human immunodeficiency virus-specific CD8+ T cell responses

Cited by 8 publications

References 54 publications

Altered Peptide Ligands Revisited: Vaccine Design through Chemically Modified HLA-A2–Restricted T Cell Epitopes

Altered Peptide Ligands Revisited: Vaccine Design through Chemically Modified HLA-A2–Restricted T Cell Epitopes

Heteroclitic Peptides Increase Proliferation and Reduce Evidence of Human Immunodeficiency Virus-Specific CD8+T Cell Dysfunction

The bright side of chemistry: Exploring synthetic peptide‐based anticancer vaccines

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Heteroclitic Peptides Increase Proliferation and Reduce Evidence of Human Immunodeficiency Virus-Specific CD8⁺T Cell Dysfunction