Definition of an HLA-A3-like supermotif demonstrates the overlapping peptide-binding repertoires of common HLA molecules

Sidney, John; Grey, Howard M.; Southwood, Scott; Celis, Esteban; Wentworth, Peggy; Guercio, Marika; Kubo, Ralph T.; Chesnut, Robert W.; Sette, Alessandro

doi:10.1016/0198-8859(95)00173-5

Cited by 192 publications

(159 citation statements)

References 59 publications

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“…This can be problematic when allele-specific epitopes are identified, but our focus on HLA supertypes is meant to overcome this potential limitation (23,48,82). To directly test this theory, we analyzed the HLA-binding affinity of the vaccine epitopes with respect to known HLA phenotype frequencies in different ethnic groups.…”

Section: Discussionmentioning

confidence: 99%

“…level of DNA typing, correspondence to serologically defined Ag frequencies was assumed (48). Gene frequencies were calculated from phenotypic frequencies utilizing the binomial distribution formulae (48).…”

Section: Calculation Of Potential Population Coveragementioning

confidence: 99%

“…Gene frequencies were calculated from phenotypic frequencies utilizing the binomial distribution formulae (48). Estimates of the redundancy or breadth of coverage afforded by a specific panel of epitopes were derived using the game theory Monte Carlo simulation methodology (49).…”

Section: Calculation Of Potential Population Coveragementioning

confidence: 99%

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Development of a DNA Vaccine Designed to Induce Cytotoxic T Lymphocyte Responses to Multiple Conserved Epitopes in HIV-1

Wilson

McKinney²,

Anders

et al. 2003

The Journal of Immunology

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Epitope-based vaccines designed to induce CTL responses specific for HIV-1 are being developed as a means for addressing vaccine potency and viral heterogeneity. We identified a set of 21 HLA-A2, HLA-A3, and HLA-B7 restricted supertype epitopes from conserved regions of HIV-1 to develop such a vaccine. Based on peptide-binding studies and phenotypic frequencies of HLA-A2, HLA-A3, and HLA-B7 allelic variants, these epitopes are predicted to be immunogenic in greater than 85% of individuals. Immunological recognition of all but one of the vaccine candidate epitopes was demonstrated by IFN-γ ELISPOT assays in PBMC from HIV-1-infected subjects. The HLA supertypes of the subjects was a very strong predictor of epitope-specific responses, but some subjects responded to epitopes outside of the predicted HLA type. A DNA plasmid vaccine, EP HIV-1090, was designed to express the 21 CTL epitopes as a single Ag and tested for immunogenicity using HLA transgenic mice. Immunization of HLA transgenic mice with this vaccine was sufficient to induce CTL responses to multiple HIV-1 epitopes, comparable in magnitude to those induced by immunization with peptides. The CTL induced by the vaccine recognized target cells pulsed with peptide or cells transfected with HIV-1 env or gag genes. There was no indication of immunodominance, as the vaccine induced CTL responses specific for multiple epitopes in individual mice. These data indicate that the EP HIV-1090 DNA vaccine may be suitable for inducing relevant HIV-1-specific CTL responses in humans.

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Section: Discussionmentioning

confidence: 99%

Section: Calculation Of Potential Population Coveragementioning

confidence: 99%

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Development of a DNA Vaccine Designed to Induce Cytotoxic T Lymphocyte Responses to Multiple Conserved Epitopes in HIV-1

Wilson

McKinney²,

Anders

et al. 2003

The Journal of Immunology

Self Cite

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“…Specific cytolytic responses are generally mediated by CD8ϩ T cell recognition of antigenic peptides in the context of major histocompatibility complex (MHC) 1 class I molecules. Recent advances in defining "supermotif" antigens capable of being presented by multiple MHC I alleles (1)(2)(3)(4) and immunodominant epitopes (5-9) will undoubtedly have a significant impact on realizing these goals. However, beyond defining appropriate antigenic peptides, a second challenge lies in establishing effective methods with which to deliver these antigens to the MHC I loading pathway.…”

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confidence: 99%

The Effect of Human β2-Microglobulin on Major Histocompatibility Complex I Peptide Loading and the Engineering of a High Affinity Variant

Shields¹,

Kubota²,

Hodgson³

et al. 1998

Journal of Biological Chemistry

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The ability to directly load cell surface major histocompatibility complex (MHC) class I molecules with peptides provides a potentially powerful approach toward the development of vaccines to generate cell-mediated immunity. We demonstrate that exogenous ␤ 2 -microglobulin (␤ 2 m) stabilizes human cell surface MHC I molecules and facilitates their loading with exogenous peptides. Additionally, using three-dimensional crystal structures and known interaction sites between MHC I heavy chains and ␤ 2 m, we engineered variants of human ␤ 2 m (h␤ 2 m) with a single serine substitution at residue 55. This alteration was predicted to promote hydrophobic interactions at the MHC I heavy chain/␤ 2 m interface and displace an ordered water molecule. Compared with h␤ 2 m, the serine to valine substitution at residue 55 had improved ability to bind to cell surface HLA-A1, HLA-A2, and HLA-A3 molecules, facilitate exogenous peptide loading, and promote recognition by peptide-specific T cells. The inclusion of h␤ 2 m or higher affinity variants when pulsing cells with MHC-restricted peptides increases the efficiency of peptide loading 50 -80-fold. Therefore, the inclusion of h␤ 2 m in peptide-based vaccines may increase cell surface antigen densities above thresholds that allow recognition of peptide antigens by the immune system, particularly for cryptic, subdominant, or marginally antigenic peptides.In the field of vaccine development, it has been relatively simple to induce humoral responses to injected antigens. However, one of the major challenges in the treatment of tumors and viral infections is the generation of vaccines that stimulate cell-mediated immune responses to these pathogens. Specific cytolytic responses are generally mediated by CD8ϩ T cell recognition of antigenic peptides in the context of major histocompatibility complex (MHC) 1 class I molecules. Recent advances in defining "supermotif" antigens capable of being presented by multiple MHC I alleles (1-4) and immunodominant epitopes (5-9) will undoubtedly have a significant impact on realizing these goals. However, beyond defining appropriate antigenic peptides, a second challenge lies in establishing effective methods with which to deliver these antigens to the MHC I loading pathway. Typically, MHC I molecules acquire peptides generated by the degradation of endogenous proteins by the proteasome. These peptides are transported into the endoplasmic reticulum, where they are bound by MHC I⅐␤ 2 -microglobulin (␤ 2 m) complexes and finally transit to the cell surface (10 -12). Although this pathway is the dominant means of loading MHC I molecules, other methods of delivering antigenic peptides to MHC I have been described including direct incorporation of DNA into cells (13-16), phagocytosis-dependent representation of antigens (17, 18), and infection by bacterial (19) or viral vectors (20, 21). All of these approaches attempt to introduce peptide into the endogenous loading pathway. Alternatively, direct cell surface loading of MHC I molecules in vitro has al...

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“…33 One such family, the HLA-A3-like supertype, comprises products from the HLA class I alleles A3, A11, A31, A*3301, A*6801. 34 Interestingly, the b3a2 junctional peptides found to bind HLA class I molecules by Bocchia et al, 16 bind to at least two members of this superfamily. In our analysis, patients with HLA-A3 or A-31 had some of the better major cytogenetic response rates, but further analysis of the significance of this will require a more precise definition of these and other supermotifs, and a larger population sample.…”

Section: Discussionmentioning

confidence: 99%

Association of HLA phenotype and response to interferon-alpha in patients with chronic myelogenous leukemia

et al. 1998

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Twenty to 25% of patients with chronic myelogenous leukemia (CML) treated with interferon-alpha (IFN-A) achieve a complete cytogenetic response (CCR). However, cells bearing rearrangement of BCR/ABL can still be detected many years after achieving a CCR despite the absence of clinical evidence of active disease. It has been suggested that the disease is kept in a dormant state by immune mechanisms. How this is achieved is not known, but it has been speculated that p210 BCR/ABL might be presented by malignant cells through HLA molecules, thus making them the target for specific immune cell killing. Because specific peptides will be expressed in association with certain HLA molecules, different HLA phenotypes could be associated with different response rates to IFN-A. The response to IFN-A-based therapies in 239 patients with chronic phase CML was analyzed according to their HLA phenotype. One hundred and ninety-four (81%) achieved complete hematologic response, 142 (59%) had a cytogenetic response which was major (MCR) in 93 patients (39%): complete (CCR) in 71 (30%) and partial (PCR) in 22 (9%). Patients with an HLA-B27 phenotype had the best response rate to IFN-A: 10 of 14 (71%) had an MCR, including eight (57%) with a CCR (P = 0.02).Patients with HLA-B35, -A3, and -A31 also showed a trend towards a higher response rate, whereas patients with HLA-B18 had the lowest response rate (MCR 17%). Patients with HLA-B27 and those with HLA-A31 showed a trend for better survival, whereas patients with HLA-A2, -B7, or -B18 had a trend for shorter survival. We conclude that response to IFN-A in patients with CML may be associated with the HLA phenotype. However, a much larger population would be required to determine if the impact of HLA phenotype on survival is independent of other clinical prognostic features. These findings could be relevant for the understanding of immune mechanisms of control of CML and possibly the design of immune therapy for this disease.

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Definition of an HLA-A3-like supermotif demonstrates the overlapping peptide-binding repertoires of common HLA molecules

Cited by 192 publications

References 59 publications

Development of a DNA Vaccine Designed to Induce Cytotoxic T Lymphocyte Responses to Multiple Conserved Epitopes in HIV-1

Development of a DNA Vaccine Designed to Induce Cytotoxic T Lymphocyte Responses to Multiple Conserved Epitopes in HIV-1

The Effect of Human β2-Microglobulin on Major Histocompatibility Complex I Peptide Loading and the Engineering of a High Affinity Variant

Association of HLA phenotype and response to interferon-alpha in patients with chronic myelogenous leukemia

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