Antagonist HIV-1 Gag Peptides Induce Structural Changes in HLA B8

Reid, S. W. J.; McAdam, Stephen N.; Smith, Kathrine J.; Klenerman, Paul; O’Callaghan, Chris; Harlos, K.; Jakobsen, Bent K.; Mcmichael, A. J.; Bell, John I.; Stuart, David I.; Jones, E Y

doi:10.1084/jem.184.6.2279

Cited by 124 publications

(92 citation statements)

References 34 publications

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“…These peptides did not affect the activation of T cell effector functions. Peptide ligands were obtained by changing nonanchor amino acids of the natural HLA-A2-presented CLG epitope (40). The differential recognition of these analogues by CTLs may be due to conformational changes affecting residues pointing out toward TCR or, alternatively, affecting the orientation of neighboring MHC side chains.…”

Section: Discussionmentioning

confidence: 99%

Supra-Agonist Peptides Enhance the Reactivation of Memory CTL Responses

Micheletti¹,

Canella²,

Vertuani³

et al. 2000

The Journal of Immunology

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Single amino acid substitutions at TCR contacts may transform a natural peptide Ag in CTL ligands with partial agonist, antagonist, or null activity. We obtained peptide variants by changing nonanchor amino acid residues involved in MHC class I binding. These peptides were derived from a subdominant HLA-A2-presented, latent membrane protein 2-derived epitope expressed in EBV-infected cells and in EBV-associated tumors. We found that small structural changes produced ligands with vastly different activities. In particular, the variants that associated more stably to HLA-A2/molecules did not activate any CTL function, behaving as null ligands. Interestingly, T cell stimulations performed with the combination of null ligands and the natural epitope produced significantly higher specific CTL reactivation than reactivation of CTLs induced by the wild-type epitope alone. In addition, these particular variants activated memory CTL responses in the presence of concentrations of natural epitope that per se did not induce T cell responses. We show here that null ligands increased ZAP-70 tyrosine kinase activation induced by the natural epitope. Our results demonstrate for the first time that particular peptide variants, apparently behaving as null ligands, interact with the TCR, showing a supra-agonist activity. These variant peptides did not affect the effector T cell functions activated by the natural epitope. Supra-agonist peptides represent the counterpart of antagonists and may have important applications in the development of therapeutic peptides.

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Section: Discussionmentioning

confidence: 99%

Supra-Agonist Peptides Enhance the Reactivation of Memory CTL Responses

Micheletti¹,

Canella²,

Vertuani³

et al. 2000

The Journal of Immunology

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“…The previously solved monomeric HLA A2 structure (Protein Data Bank code 1DUY) (33), minus the peptide, was used as the search probe. A clear peak in the rotation function yielded one clear solution in the translation function that packed well within the unit cell.…”

Section: Methodsmentioning

confidence: 99%

Functional and Structural Characteristics of NY-ESO-1-related HLA A2-restricted Epitopes and the Design of a Novel Immunogenic Analogue

Webb

Dunstone

Chen

et al. 2004

Journal of Biological Chemistry

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NY-ESO-1, a commonly expressed tumor antigen of the cancer-testis family, is expressed by a wide range of tumors but not found in normal adult somatic tissue, making it an ideal cancer vaccine candidate. Peptides derived from NY-ESO-1 have shown preclinical and clinical trial promise; however, biochemical features of these peptides have complicated their formulation and led to heterogeneous immune responses. We have taken a rational approach to engineer an HLA A2-restricted NY-ESO-1-derived T cell epitope with improved formulation and immunogenicity to the wild type peptide. To accomplish this, we have solved the x-ray crystallographic structures of HLA A2 complexed to NY-ESO (157-165) and two analogues of this peptide in which the C-terminal cysteine residue has been substituted to alanine or serine. Substitution of cysteine by serine maintained peptide conformation yet reduced complex stability, resulting in poor cytotoxic T lymphocyte recognition. Conversely, substitution with alanine maintained complex stability and cytotoxic T lymphocyte recognition. Based on the structures of the three HLA A2 complexes, we incorporated 2-aminoisobutyric acid, an isostereomer of cysteine, into the epitope. This analogue is impervious to oxidative damage, cysteinylation, and dimerization of the peptide epitope upon formulation that is characteristic of the wild type peptide. Therefore, this approach has yielded a potential therapeutic molecule that satiates the hydrophobic F pocket of HLA A2 and exhibited superior immunogenicity relative to the wild type peptide.Class I major histocompatibility complex (MHC) 1 molecules play a crucial role in immune surveillance by selectively binding to intracellular peptide antigens (Ag) and presenting them at the cell surface to CD8 ϩ T lymphocytes (T CD8 ), including cytotoxic T lymphocytes (CTL). Eradication of tumors is associated with a robust cytotoxic T cell response to antigens expressed by the tumor (tumor-associated antigens (TAA)). Because many TAA are self-proteins or closely related to selfproteins, they tend to be poorly immunogenic (1-5). Moreover, many TAA-derived peptides are not strong binders to class I molecules, making strategies that revolve around tumor Ag delivery poor inducers of CD8 T cell immunity (6). Synthetic peptide-based vaccines offer a flexible, relatively simple and cost-effective way to treat a variety of human diseases, including the immunotherapy of cancer. Moreover, synthetic peptides are easily engineered to improve the efficacy of the immunogen. Such engineering may include optimizing target MHC class I binding by substituting key residues with more appropriate anchor residues. In addition, peptide-based therapeutics can be engineered to improve formulation and storage properties, and strategies exist to protect labile peptide bonds by incorporating nonpeptidic structures (7-11). Several studies have incorporated nonnatural amino acids in peptidic structures to improve compound stability and maintain T cell cross-reactivity. For example, some studie...

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“…Results are expressed as percent HLA-B8 reconstitution. Only the control peptide and E7 [7][8][9][10][11][12][13][14][15] and E7 75-82 were able to reconstitute empty HLA-B8 heavy-chain complexes above 10% (acid-stripped) cell surface expression on C1R-B8 cells. Data are representative of 5 independent experiments; 10,000 events were counted per peptide concentration.…”

Section: Tetramer In Situ Stainingmentioning

confidence: 99%

“…Until now, HLA-B8-restricted and HPV-specific T-cell responses have not been identified. HLA-B8 has been described to present peptides to T cells directed against human immunodeficiency virus (HIV) [11][12][13] or Epstein-Barr virus (EBV). 14,15 HLA-B8 also appears to play a role in progression to AIDS in HIV-infected individuals 16 and in reduced antibody titers against EBV.…”

mentioning

confidence: 99%

Naturally processed and HLA‐B8‐presented HPV16 E7 epitope recognized by T cells from patients with cervical cancer

Oerke¹,

Höhn²,

Zehbe³

et al. 2005

Intl Journal of Cancer

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Several major histocompatibility complex (MHC) alleles have been reported to present peptides derived from the HPV16 E7 oncoprotein to T cells. We describe an overrepresentation of the HLA-B8 allele (28.44%) in cervical cancer patients as compared to the MHC class I allele frequency in a local healthy control population (18.80%) and the identification of an HLA-B8-binding peptide TLHEYMLDL (HPV16 E7 7-15 ), which is able to drive HPV16 E7-specific and MHC class I-restricted T-cell responses in peripheral blood lymphocytes from healthy individuals. TLHEYMLDLspecific T cells recognize the naturally processed and presented peptide on HPV16؉ cervical cancer cells transfected with the HLA-B8 gene defined by IFN-␥ production. This peptide epitope is also recognized by freshly harvested tumor-infiltrating T cells or T cells from tumor-draining lymph nodes from patients with cervical cancer determined by flow cytometry as well as by tetramer in situ staining. HLA-B8-restricted HPV E7 7-15 -specific T cells reside predominantly in the CD8 ؉ CD45RA ؉ CCR7 ؉ precursor or in the differentiated CD8 ؉ CD45RA ؉ CCR7 ؊ T-cell population.

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Antagonist HIV-1 Gag Peptides Induce Structural Changes in HLA B8

Cited by 124 publications

References 34 publications

Supra-Agonist Peptides Enhance the Reactivation of Memory CTL Responses

Supra-Agonist Peptides Enhance the Reactivation of Memory CTL Responses

Functional and Structural Characteristics of NY-ESO-1-related HLA A2-restricted Epitopes and the Design of a Novel Immunogenic Analogue

Naturally processed and HLA‐B8‐presented HPV16 E7 epitope recognized by T cells from patients with cervical cancer

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