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1.  Relation of HLA Class I and II Supertypes with Spontaneous Clearance of Hepatitis C Virus 
Genes and immunity  2013;14(5):330-335.
Human leukocyte antigen (HLA) genotype has been associated with probability of spontaneous clearance of hepatitis C virus (HCV). However, no prior studies have examined whether this relationship may be further characterized by grouping HLA alleles according to their supertypes, defined by their binding capacities. There is debate regarding the most appropriate method to define supertypes. Therefore, previously reported HLA supertypes (46 class I and 25 class II) were assessed for their relation with HCV clearance in a population of 758 HCV-seropositive women. Two HLA class II supertypes were significant in multivariable models that included: (i) supertypes with significant or borderline associations with HCV clearance after adjustment for multiple tests, and (ii) individual HLA alleles not part of these supertypes, but associated with HCV clearance in our prior study in this population. Specifically, supertype DRB3 (prevalence ratio (PR)=0.4; p=0.004) was associated with HCV persistence while DR8 (PR=1.8; p=0.01) was associated with HCV clearance. Two individual alleles (B*57:01 and C*01:02) associated with HCV clearance in our prior study became non-significant in analysis that included supertypes while B*57:03 (PR=1.9; p=0.008) and DRB1*07:01 (PR=1.7; p=0.005) retained significance. These data provide epidemiologic support for the significance of HLA supertypes in relation to HCV clearance.
doi:10.1038/gene.2013.25
PMCID: PMC3723800  PMID: 23636221
hepatitis C virus; HLA; human leukocyte antigen; supertype
2.  HLA Alleles Association with Changes in Bone Mineral Density in HIV-1-Infected Adults Changing Treatment to Tenofovir-Emtricitabine or Abacavir-Lamivudine 
PLoS ONE  2014;9(3):e93333.
Background
There are limited data regarding the influence of human leukocyte antigen (HLA) polymorphisms on reduced bone mineral density (BMD). We investigated the relationship between HLA supertypes and BMD in HIV-infected adults changing their existing treatment to tenofovir-emtricitabine (TDF-FTC) or abacavir-lamivudine (ABC-3TC) in the STEAL study.
Methods
Lumbar spine and right hip BMD were measured by Dual-energy X-ray absorptiometry (DXA). HLA genotypes at the 2-digit level were classified into class I and II supertypes. Student's t-tests were used to test the association between HLA supertypes and changes in hip and spine BMD over 96 weeks for the whole cohort and stratified by randomised groups. The relationship between HLA supertypes and BMD was also assessed in the subgroup of participants that were naïve to both ABC and TDF at study entry.
Results
Class II supertypes were mainly associated with hip BMD change. Overall, compared to participants not carrying HLA-DQ3, participants expressing DQ3 had less bone loss over 96 weeks at both the hip and spine (hip: 0.003 vs. −0.006 g/cm2, 95%CI 0.002 to 0.017, p = 0.016; spine: 0.006 vs. −0.006 g/cm2, 95%CI 0.001 to 0.023, p = 0.041). In participants that were naïve to both ABC and TDF at baseline and randomised to TDF-FTC, DQ3 was significantly associated with less bone loss compared with those not carrying DQ3 (hip: 0.001 vs. −0.032 g/cm2; diff 0.033; 95%CI 0.017 to 0.049; p<0.001; spine: 0.007 vs. −0.023 g/cm2; diff 0.035; 95%CI 0.014 to 0.056; p = 0.001).
Conclusions
In this cohort of HIV-infected adults, there was an association between bone status and HLA supertypes, particularly HLA-DQ3.
Trial Registration
Clinicaltrials.gov NCT00192634
doi:10.1371/journal.pone.0093333
PMCID: PMC3969319  PMID: 24681993
3.  Functional analysis of frequently expressed Chinese rhesus macaque MHC class I molecules Mamu-A1*02601 and Mamu-B*08301 reveals HLA-A2 and HLA-A3 supertypic specificities 
Immunogenetics  2011;63(5):275-290.
The Simian immunodeficiency virus (SIV)-infected Indian rhesus macaque (Macaca mulatta) is the most established model of HIV infection and AIDS-related research, despite the potential that macaques of Chinese origin is a more relevant model. Ongoing efforts to further characterize the Chinese rhesus macaques’ major histocompatibility complex (MHC) for composition and function should facilitate greater utilization of the species. Previous studies have demonstrated that Chinese-origin M. mulatta (Mamu) class I alleles are more polymorphic than their Indian counterparts, perhaps inferring a model more representative of human MHC, human leukocyte antigen (HLA). Furthermore, the Chinese rhesus macaque class I allele Mamu-A1*02201, the most frequent allele thus far identified, has recently been characterized and shown to be an HLA-B7 supertype analog, the most frequent supertype in human populations. In this study, we have characterized two additional alleles expressed with high frequency in Chinese rhesus macaques, Mamu-A1*02601 and Mamu-B*08301. Upon the development of MHC–peptide-binding assays and definition of their associated motifs, we reveal that these Mamu alleles share peptide-binding characteristics with the HLA-A2 and HLA-A3 supertypes, respectively, the next most frequent human supertypes after HLA-B7. These data suggest that Chinese rhesus macaques may indeed be a more representative model of HLA gene diversity and function as compared to the species of Indian origin and therefore a better model for investigating human immune responses.
Electronic supplementary material
The online version of this article (doi:10.1007/s00251-010-0502-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s00251-010-0502-8
PMCID: PMC3068250  PMID: 21274527
HLA supertype; MHC; Peptide-binding motif; Rhesus macaque
4.  Selection of epitope-based vaccine targets of HCV genotype 1 of Asian origin: a systematic in silico approach 
Bioinformation  2012;8(20):957-962.
Hepatitis C is the major health problem over the globe affecting approximately 200 million people worldwide and about 10 million Pakistani populations. Developing countries are especially facing the problems of HCV infection. Hence the goal of the study was to find out the antigenic epitopes that could be effective vaccine targets of HCV genotype 1 of Asian origin against HLA alleles frequently distributed in Asian countries. A total of 85 complete genome sequences of HCV 1 of Asian origin were retrieved from the HCV sequence database. Using in silico tools, T cell epitopes were predicted from conserved regions of all the available HCV 1 subtypes against Asian HLA alleles. Using 10 MHC I supertypes 51 epitopes was predicted as promiscuous binders. MHC class I supertypes A2 and B7 were found to be good promiscuous binders for a large number of predicted epitopes. Other alleles of MHC I supertypes (B57, B27, BX, B44) either were not respondent as promiscuous binders or responded only to a limited number of epitopes. Against 8 predominantly found Asian alleles of DRB1 supertype, 42 epitopes was predicted as promiscuous binders. MHC class II alleles DRB1-0101, DRB1-0701 and DRB1-1501 were the highest binders to promiscuous predicted epitopes while DRB1-0301 was the least binder for the predicted promiscuous epitopes of HCV 1 genotype of Asian origin. Literature review survey of predicted epitopes via IEDB also confirmed that great numbers of predicted epitopes are true positive. Hence, sophisticated selection of viral proteins and MHCs provided conserved promiscuous epitopes that can be used as effective vaccine candidates for all Asian counties.
Abbreviations
HCV - hepatitis C virus, MHC - major histocompatability complex, HLA - human leukocyte antigen, CTL - cytotoxic T lymphocytes.
doi:10.6026/97320630008957
PMCID: PMC3524940  PMID: 23275687
Hepatitus C Virus; Immunoinformatics; MHC; Epitope; Conservancy; Asia
5.  Human Leukocyte Antigen B58 Supertype and Human Immunodeficiency Virus Type 1 Infection in Native Africans 
Journal of Virology  2006;80(12):6056-6060.
Human leukocyte antigen (HLA) class I alleles can be grouped into supertypes according to their shared peptide binding properties. We examined alleles of the HLA-B58 supertype (B58s) in treatment-naïve human immunodeficiency virus type 1 (HIV-1)-seropositive Africans (423 Zambians and 202 Rwandans). HLA-B and HLA-C alleles were resolved to four digits by a combination of molecular methods, and their respective associations with outcomes of HIV-1 infection were analyzed by statistical procedures appropriate for continuous or categorical data. The effects of the individual alleles on natural HIV-1 infection were heterogeneous. In HIV-1 subtype C-infected Zambians, the mean viral load (VL) was lower among B*5703 (P = 0.01) or B*5703-Cw*18 (P < 0.001) haplotype carriers and higher among B*5802 (P = 0.02) or B*5802-Cw*0602 (P = 0.03) carriers. The B*5801-Cw*03 haplotype showed an association with low VL (P = 0.05), whereas B*5801 as a whole did not. Rwandans with HIV-1 subtype A infection showed associations of B*5703 and B*5802 with slow (P = 0.06) and rapid (P = 0.003) disease progression, respectively. In neither population were B*1516-B*1517 alleles associated with more favorable responses. Overall, B58s alleles, individually or as part of an HLA-B-HLA-C haplotype, appeared to have a distinctive impact on HIV-1 infection among native Africans. As presently defined, B58s alleles cannot be considered uniformly protective against HIV/AIDS in every population.
doi:10.1128/JVI.02119-05
PMCID: PMC1472610  PMID: 16731944
6.  HLA Class I-T Cell Epitopes from trans-Sialidase Proteins Reveal Functionally Distinct Subsets of CD8+ T Cells in Chronic Chagas Disease 
Background
Previously, we identified a set of HLA-A020.1-restricted trans-sialidase peptides as targets of CD8+ T cell responses in HLA-A0201+ individuals chronically infected by T. cruzi.
Methods and Findings
Herein, we report the identification of peptides encoded by the same trans-sialidase gene family that bind alleles representative of the 6 most common class I HLA-supertypes. Based on a combination of bioinformatic predictions and HLA-supertype considerations, a total of 1001 epitopes predicted to bind to HLA A01, A02, A03, A24, B7 and B44 supertypes was selected. Ninety-six supertype-binder epitopes encoded by multiple trans-sialidase genes were tested for the ability to stimulate a recall CD8+ T cell response in the peripheral blood from subjects with chronic T. cruzi infection regardless the HLA haplotype. An overall hierarchy of antigenicity was apparent, with the A02 supertype peptides being the most frequently recognized in the Chagas disease population followed by the A03 and the A24 supertype epitopes. CD8+ T cell responses to promiscuous epitopes revealed that the CD8+ T cell compartment specific for T. cruzi displays a functional profile with T cells secreting interferon-γ alone as the predominant pattern and very low prevalence of single IL-2-secreting or dual IFN-γ/IL-2 secreting T cells denoting a lack of polyfunctional cytokine responses in chronic T. cruzi infection.
Conclusions
This study identifies a set of T. cruzi peptides that should prove useful for monitoring immune competence and changes in infection and disease status in individuals with chronic Chagas disease.
Author Summary
At present, 16–20 million people in Central and South America are infected with Trypanosoma cruzi, the causative agent of Chagas disease in humans. The primary clinical consequence of the infection is a cardiomyopathy, which manifests in approximately 30% of infected individuals, many years after the initial infection. Our work in Chagas disease patients began as an effort to assess the range and specificity of antigens that were recognized by T cells, in particular CD8+ T cells, in individuals with long-term infections with Trypanosoma cruzi. Trans-sialidase proteins from T. cruzi are major surface and released proteins that are targets of humoral and cellular immune responses. We previously, identified a set of trans-sialidase peptides that were recognized by a very low frequency of chronically T. cruzi-infected subjects. Based on bioinformatic predictions, herein we report the identification of new trans-sialidase epitopes that are recognized by a higher proportion of T. cruzi-infected people. The functional profile of T cells specific for these peptides is characteristic of an infection with long term stimulation of the immune system, with high levels of IFN-γ-secreting T cells and low levels of IL-2 production. This set of T. cruzi peptides should prove useful for monitoring immune competence and changes in infection and disease status in individuals with chronic Chagas disease.
doi:10.1371/journal.pntd.0000288
PMCID: PMC2565697  PMID: 18846233
7.  HLA class I supertypes: a revised and updated classification 
BMC Immunology  2008;9:1.
Background
Class I major histocompatibility complex (MHC) molecules bind, and present to T cells, short peptides derived from intracellular processing of proteins. The peptide repertoire of a specific molecule is to a large extent determined by the molecular structure accommodating so-called main anchor positions of the presented peptide. These receptors are extremely polymorphic, and much of the polymorphism influences the peptide-binding repertoire. However, despite this polymorphism, class I molecules can be clustered into sets of molecules that bind largely overlapping peptide repertoires. Almost a decade ago we introduced this concept of clustering human leukocyte antigen (HLA) alleles and defined nine different groups, denominated as supertypes, on the basis of their main anchor specificity. The utility of this original supertype classification, as well several other subsequent arrangements derived by others, has been demonstrated in a large number of epitope identification studies.
Results
Following our original approach, in the present report we provide an updated classification of HLA-A and -B class I alleles into supertypes. The present analysis incorporates the large amount of class I MHC binding data and sequence information that has become available in the last decade. As a result, over 80% of the 945 different HLA-A and -B alleles examined to date can be assigned to one of the original nine supertypes. A few alleles are expected to be associated with repertoires that overlap multiple supertypes. Interestingly, the current analysis did not identify any additional supertype specificities.
Conclusion
As a result of this updated analysis, HLA supertype associations have been defined for over 750 different HLA-A and -B alleles. This information is expected to facilitate epitope identification and vaccine design studies, as well as investigations into disease association and correlates of immunity. In addition, the approach utilized has been made more transparent, allowing others to utilize the classification approach going forward.
doi:10.1186/1471-2172-9-1
PMCID: PMC2245908  PMID: 18211710
8.  Hotspot Hunter: a computational system for large-scale screening and selection of candidate immunological hotspots in pathogen proteomes 
BMC Bioinformatics  2008;9(Suppl 1):S19.
Background
T-cell epitopes that promiscuously bind to multiple alleles of a human leukocyte antigen (HLA) supertype are prime targets for development of vaccines and immunotherapies because they are relevant to a large proportion of the human population. The presence of clusters of promiscuous T-cell epitopes, immunological hotspots, has been observed in several antigens. These clusters may be exploited to facilitate the development of epitope-based vaccines by selecting a small number of hotspots that can elicit all of the required T-cell activation functions. Given the large size of pathogen proteomes, including of variant strains, computational tools are necessary for automated screening and selection of immunological hotspots.
Results
Hotspot Hunter is a web-based computational system for large-scale screening and selection of candidate immunological hotspots in pathogen proteomes through analysis of antigenic diversity. It allows screening and selection of hotspots specific to four common HLA supertypes, namely HLA class I A2, A3, B7 and class II DR. The system uses Artificial Neural Network and Support Vector Machine methods as predictive engines. Soft computing principles were employed to integrate the prediction results produced by both methods for robust prediction performance. Experimental validation of the predictions showed that Hotspot Hunter can successfully identify majority of the real hotspots. Users can predict hotspots from a single protein sequence, or from a set of aligned protein sequences representing pathogen proteome. The latter feature provides a global view of the localizations of the hotspots in the proteome set, enabling analysis of antigenic diversity and shift of hotspots across protein variants. The system also allows the integration of prediction results of the four supertypes for identification of hotspots common across multiple supertypes. The target selection feature of the system shortlists candidate peptide hotspots for the formulation of an epitope-based vaccine that could be effective against multiple variants of the pathogen and applicable to a large proportion of the human population.
Conclusion
Hotspot Hunter is publicly accessible at . It is a new generation computational tool aiding in epitope-based vaccine design.
doi:10.1186/1471-2105-9-S1-S19
PMCID: PMC2259420  PMID: 18315850
9.  Functional classification of class II human leukocyte antigen (HLA) molecules reveals seven different supertypes and a surprising degree of repertoire sharing across supertypes 
Immunogenetics  2011;63(6):325-335.
Previous studies have attempted to define human leukocyte antigen (HLA) class II supertypes, analogous to the case for class I, on the basis of shared peptide-binding motifs or structure. In the present study, we determined the binding capacity of a large panel of non-redundant peptides for a set of 27 common HLA DR, DQ, and DP molecules. The measured binding data were then used to define class II supertypes on the basis of shared binding repertoires. Seven different supertypes (main DR, DR4, DRB3, main DQ, DQ7, main DP, and DP2) were defined. The molecules associated with the respective supertypes fell largely along lines defined by MHC locus and reflect, in broad terms, commonalities in reported peptide-binding motifs. Repertoire overlaps between molecules within the same class II supertype were found to be similar in magnitude to what has been observed for HLA class I supertypes. Surprisingly, however, the degree to which repertoires between molecules in the different class II supertypes also overlapped was found to be five to tenfold higher than repertoire overlaps noted between molecules in different class I supertypes. These results highlight a high degree of repertoire overlap amongst all HLA class II molecules, perhaps reflecting binding in multiple registers, and more pronounced dependence on backbone interactions rather than peptide anchor residues. This fundamental difference between HLA class I and class II would not have been predicted on the basis of analysis of either binding motifs or the sequence/predicted structures of the HLA molecules.
doi:10.1007/s00251-011-0513-0
PMCID: PMC3626422  PMID: 21305276
MHC; HLA class I; HLA class II; Peptide binding; T cell epitopes
10.  Adaptive interactions between HLA and HIV-1: Highly divergent selection imposed by HLA class I molecules with common supertype motifs1 
Currently 1.1 million individuals in the United States of America are living with HIV-1 infection. While this is a relatively small proportion of the global pandemic, the remarkable mix of ancestries in the U.S.A, drawn together over the past two centuries of continuous population migrations, provides an important and unique perspective on adaptive interactions between HIV-1 and human genetic diversity. HIV-1 is a rapidly adaptable organism and mutates within or near immune epitopes which are determined by the human leukocyte antigen (HLA) class I genotype of the infected host. We characterized HLA-associated polymorphisms across the full HIV-1 proteome in a large, ethnically diverse, national U.S cohort of HIV-1 infected individuals. We found a striking divergence in the immunoselection patterns associated with HLA variants which have very similar or identical peptide binding specificities but are differentially distributed among racial/ethnic groups. Though their similarity in peptide binding functionally clusters these HLA variants into supertypes, their differences at sites within the peptide binding groove contributes to ‘race-specific’ selection effects on circulating HIV-1 viruses. This suggests that the interactions between the HLA/HIV peptide complex and the T cell receptor (TCR) varies significantly within HLA supertype groups, which in turn, influences HIV-1 evolution.
doi:10.4049/jimmunol.0903745
PMCID: PMC3011274  PMID: 20231689
11.  Association between Virus-Specific T-Cell Responses and Plasma Viral Load in Human Immunodeficiency Virus Type 1 Subtype C Infection 
Journal of Virology  2003;77(2):882-890.
Virus-specific T-cell immune responses are important in restraint of human immunodeficiency virus type 1 (HIV-1) replication and control of disease. Plasma viral load is a key determinant of disease progression and infectiousness in HIV infection. Although HIV-1 subtype C (HIV-1C) is the predominant virus in the AIDS epidemic worldwide, the relationship between HIV-1C-specific T-cell immune responses and plasma viral load has not been elucidated. In the present study we address (i) the association between the level of plasma viral load and virus-specific immune responses to different HIV-1C proteins and their subregions and (ii) the specifics of correlation between plasma viral load and T-cell responses within the major histocompatibility complex (MHC) class I HLA supertypes. Virus-specific immune responses in the natural course of HIV-1C infection were analyzed in the gamma interferon (IFN-γ)-enzyme-linked immunospot assay by using synthetic overlapping peptides corresponding to the HIV-1C consensus sequence. For Gag p24, a correlation was seen between better T-cell responses and lower plasma viral load. For Nef, an opposite trend was observed where a higher T-cell response was more likely to be associated with a higher viral load. At the level of the HLA supertypes, a lower viral load was associated with higher T-cell responses to Gag p24 within the HLA A2, A24, B27, and B58 supertypes, in contrast to the absence of such a correlation within the HLA B44 supertype. The present study demonstrated differential correlations (or trends to correlation) in various HIV-1C proteins, suggesting (i) an important role of the HIV-1C Gag p24-specific immune responses in control of viremia and (ii) more rapid viral escape from immune responses to Nef with no restraint of plasma viral load. Correlations between the level of IFN-γ-secreting T cells and viral load within the MHC class I HLA supertypes should be considered in HIV vaccine design and efficacy trials.
doi:10.1128/JVI.77.2.882-890.2003
PMCID: PMC140844  PMID: 12502804
12.  Peptide binding motifs associated with MHC molecules common in Chinese rhesus macaques are analogous to those of human HLA supertypes, and include HLA-B27-like alleles 
Immunogenetics  2013;65(5):371-386.
Chinese rhesus macaques are of particular interest in SIV/HIV research as these animals have prolonged kinetics of disease progression to AIDS, compared to their Indian counterparts, suggesting that they may be a better model for HIV. Nevertheless, the specific mechanism(s) accounting for these kinetics remains unclear. The study of Major Histocompatibility Complex (MHC) molecules, including their MHC:peptide binding motifs, provides valuable information for measuring cellular immune responses and deciphering outcomes of infection and vaccine efficacy. In this study, we have provided detailed characterization of six prevalent Chinese rhesus macaque MHC class I alleles, yielding a combined phenotypic frequency of 29%. The peptide binding specificity of two of these alleles, Mamu-A2*01:02 and -B*010:01, as well as the previously characterized allele Mamu-B*003:01 (and Indian rhesus Mamu-B*003:01), was found to be analogous to that of alleles in the HLA-B27 supertype family. Specific alleles in the HLA-B27 supertype family, including HLA-B*27:05, have been associated with long-term non-progression to AIDS in humans. All six alleles characterized in the present study were found to have specificities analogous to HLA-supertype alleles. These data contribute to the concept that Chinese rhesus macaque MHC immunogenetics is more similar to HLA than their Indian rhesus macaque counterparts, and thereby warrant further studies to decipher the role of these alleles in the context of SIV infection.
doi:10.1007/s00251-013-0686-9
PMCID: PMC3633659  PMID: 23417323
MHC; non-human primate; Chinese rhesus macaques; MHC:peptide binding motif
13.  Identification of Lck-derived peptides applicable to anti-cancer vaccine for patients with human leukocyte antigen-A3 supertype alleles 
British Journal of Cancer  2007;97(12):1648-1654.
The identification of peptide vaccine candidates to date has been focused on human leukocyte antigen (HLA)-A2 and -A24 alleles. In this study, we attempted to identify cytotoxic T lymphocyte (CTL)-directed Lck-derived peptides applicable to HLA-A11+, -A31+, or -A33+ cancer patients, because these HLA-A alleles share binding motifs, designated HLA-A3 supertype alleles, and because the Lck is preferentially expressed in metastatic cancer. Twenty-one Lck-derived peptides were prepared based on the binding motif to the HLA-A3 supertype alleles. They were first screened for their recognisability by immunoglobulin G (IgG) in the plasma of prostate cancer patients, and the selected candidates were subsequently tested for their potential to induce peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A3 supertype+ cancer patients. As a result, four Lck peptides were frequently recognised by IgGs, and three of them – Lck90−99, Lck449−458, and Lck450−458 – efficiently induced peptide-specific and cancer-reactive CTLs. Their cytotoxicity towards cancer cells was mainly ascribed to HLA class I-restricted and peptide-specific CD8+ T cells. These results indicate that these three Lck peptides are applicable to HLA-A3 supertype+ cancer patients, especially those with metastasis. This information could facilitate the development of peptide-based anti-cancer vaccine for patients with alleles other than HLA-A2 and -A24.
doi:10.1038/sj.bjc.6604071
PMCID: PMC2360277  PMID: 18043580
Lck; cytotoxic T lymphocyte; peptide; HLA-A3 supertype
14.  HLA-B∗44 Is Associated with Dengue Severity Caused by DENV-3 in a Brazilian Population 
Journal of Tropical Medicine  2013;2013:648475.
Human leukocyte antigen (HLA) alleles have been correlated with susceptibility or resistance to severe dengue; however, few immunogenetic studies have been performed in Latin American (LA) populations. We have conducted immunogenetic studies of HLA class I and II alleles in a cohort of 187 patients with DENV-3 infection and confirmed clinical diagnosis of either severe dengue, known as dengue hemorrhagic fever (DHF), or the less severe form, dengue fever (DF), in Recife, Pernambuco, Brazil. An association analysis was performed using Fisher's association test, with odds ratios (ORs) calculated using conditional maximum likelihood estimates. HLA-B∗44 (P = 0.047, OR = 2.025, 95% CI = 0.97–4.24) was found to be associated with increased susceptibility to DHF in response to DENV-3 infection. In addition, HLA-B∗07 (P = 0.048, OR = 0.501, one-sided 95% CI = 0–0.99) and HLA-DR∗13 (P = 0.028, OR = 0.511, one-sided 95% CI = 0–0.91) were found to be associated with resistance to secondary dengue infection by DENV-3. These results suggest that HLA-B∗44 supertype alleles and their respective T-cell responses might be involved in susceptibility to severe dengue infections, whereas the HLA-B∗07 supertype alleles and DR∗13 might be involved in cross-dengue serotype immunity.
doi:10.1155/2013/648475
PMCID: PMC3684019  PMID: 23818909
15.  MULTIPRED2: a computational system for large-scale identification of peptides predicted to bind to HLA supertypes and alleles 
Journal of immunological methods  2010;374(1-2):53-61.
MULTIPRED2 is a computational system for facile prediction of peptide binding to multiple alleles belonging to human leukocyte antigen (HLA) class I and class II DR molecules. It enables prediction of peptide binding to products of individual HLA alleles, combination of alleles, or HLA supertypes. NetMHCpan and NetMHCIIpan are used as prediction engines. The 13 HLA Class I supertypes are A1, A2, A3, A24, B7, B8, B27, B44, B58, B62, C1, and C4. The 13 HLA Class II DR supertypes are DR1, DR3, DR4, DR6, DR7, DR8, DR9, DR11, DR12, DR13, DR14, DR15, and DR16. In total, MULTIPRED2 enables prediction of peptide binding to 1077 variants representing 26 HLA supertypes. MULTIPRED2 has visualization modules for mapping promiscuous T-cell epitopes as well as those regions of high target concentration – referred to as T-cell epitope hotspots. Novel graphic representations are employed to display the predicted binding peptides and immunological hotspots in an intuitive manner and also to provide a global view of results as heat maps. Another function of MULTIPRED2, which has direct relevance to vaccine design, is the calculation of population coverage. Currently it calculates population coverage in five major groups in North America. MULTIPRED2 is an important tool to complement wet-lab experimental methods for identification of T-cell epitopes. It is available at http://cvc.dfci.harvard.edu/multipred2/.
doi:10.1016/j.jim.2010.11.009
PMCID: PMC3090484  PMID: 21130094
T-cell epitope hotspots; HLA; HLA supertype; Human Leukocyte Antigen; promiscuous binding peptide; vaccine design
16.  PEPVAC: a web server for multi-epitope vaccine development based on the prediction of supertypic MHC ligands 
Nucleic Acids Research  2005;33(Web Server issue):W138-W142.
Prediction of peptide binding to major histocompatibility complex (MHC) molecules is a basis for anticipating T-cell epitopes, as well as epitope discovery-driven vaccine development. In the human, MHC molecules are known as human leukocyte antigens (HLAs) and are extremely polymorphic. HLA polymorphism is the basis of differential peptide binding, until now limiting the practical use of current epitope-prediction tools for vaccine development. Here, we describe a web server, PEPVAC (Promiscuous EPitope-based VACcine), optimized for the formulation of multi-epitope vaccines with broad population coverage. This optimization is accomplished through the prediction of peptides that bind to several HLA molecules with similar peptide-binding specificity (supertypes). Specifically, we offer the possibility of identifying promiscuous peptide binders to five distinct HLA class I supertypes (A2, A3, B7, A24 and B15). We estimated the phenotypic population frequency of these supertypes to be 95%, regardless of ethnicity. Targeting these supertypes for promiscuous peptide-binding predictions results in a limited number of potential epitopes without compromising the population coverage required for practical vaccine design considerations. PEPVAC can also identify conserved MHC ligands, as well as those with a C-terminus resulting from proteasomal cleavage. The combination of these features with the prediction of promiscuous HLA class I ligands further limits the number of potential epitopes. The PEPVAC server is hosted by the Dana-Farber Cancer Institute at the site .
doi:10.1093/nar/gki357
PMCID: PMC1160118  PMID: 15980443
17.  Consensus classification of human leukocyte antigen class II proteins 
Immunogenetics  2012;65(2):97-105.
Class II human leukocyte antigens (HLA II) are proteins involved in the human immunological adaptive response by binding and exposing some pre-processed, non-self peptides in the extracellular domain in order to make them recognizable by the CD4+ T lymphocytes. However, the understanding of HLA–peptide binding interaction is a crucial step for designing a peptide-based vaccine because the high rate of polymorphisms in HLA class II molecules creates a big challenge, even though the HLA II proteins can be grouped into supertypes, where members of different class bind a similar pool of peptides. Hence, first we performed the supertype classification of 27 HLA II proteins using their binding affinities and structural-based linear motifs to create a stable group of supertypes. For this purpose, a well-known clustering method was used, and then, a consensus was built to find the stable groups and to show the functional and structural correlation of HLA II proteins. Thus, the overlap of the binding events was measured, confirming a large promiscuity within the HLA II–peptide interactions. Moreover, a very low rate of locus-specific binding events was observed for the HLA-DP genetic locus, suggesting a different binding selectivity of these proteins with respect to HLA-DR and HLA-DQ proteins. Secondly, a predictor based on a support vector machine (SVM) classifier was designed to recognize HLA II-binding peptides. The efficiency of prediction was estimated using precision, recall (sensitivity), specificity, accuracy, F-measure, and area under the ROC curve values of random subsampled dataset in comparison with other supervised classifiers. Also the leave-one-out cross-validation was performed to establish the efficiency of the predictor. The availability of HLA II–peptide interaction dataset, HLA II-binding motifs, high-quality amino acid indices, peptide dataset for SVM training, and MATLAB code of the predictor is available at http://sysbio.icm.edu.pl/HLA.
Electronic supplementary material
The online version of this article (doi:10.1007/s00251-012-0665-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s00251-012-0665-6
PMCID: PMC3543608  PMID: 23229472
MHC; HLA class II; Peptide binding; T cell epitopes; Clustering; Machine learning
18.  Identification and characterization of merozoite surface protein 1 epitope 
Bioinformation  2009;4(1):1-5.
Malaria is an important tropical infection which urgently requires intervention of an effective vaccine. Antigenic variations of the parasite and allelic diversity of the host are main problems in the development of an effective malaria vaccine. Cytotoxic T lymphocytes (CTL) directed against Plasmodium falciparum­derived antigens are shown to play an important role for the protection against malaria. The merozoite surface protein 1 (MSP1) is expressed in all the four life-cycle stages of Plasmodium falciparum and did not find any sequence similarity to human and mouse reference proteins. MSP1 is a known target of the immune response and a single CTL epitope binding to the HLA­A*0201 is available for merozoite form. Here, we report the results from the computational characterization of MSP1, precursor (1720 residue) and screening of highest scoring potential CTL epitopes for 1712 overlapping peptides binding to thirty four HLA class­I alleles and twelve HLA class­I supertypes (5 HLA­A and 7 HLA­B) using bioinformatics tools. Supertypes are the clustered groups of HLA class­I molecules, representing a sets of molecules that share largely overlapping peptide binding specificity. The prediction results for MSP1 as adhesin and adhesin-like in terms of probability is 1.0. Results also show that MSP1 has orthologs to other related species as well as having non allergenicity and single transmembrane properties demonstrating its suitability as a vaccine candidate. The predicted peptides are expected to be useful in the design of multi-epitope vaccines without compromising the human population coverage.
PMCID: PMC2770364  PMID: 20011145
epitope; supertype; vaccine; malaria; bioinformatics
19.  Human immunome, bioinformatic analyses using HLA supermotifs and the parasite genome, binding assays, studies of human T cell responses, and immunization of HLA-A*1101 transgenic mice including novel adjuvants provide a foundation for HLA-A03 restricted CD8+T cell epitope based, adjuvanted vaccine protective against Toxoplasma gondii 
Immunome Research  2010;6:12.
Background
Toxoplasmosis causes loss of life, cognitive and motor function, and sight. A vaccine is greatly needed to prevent this disease. The purpose of this study was to use an immmunosense approach to develop a foundation for development of vaccines to protect humans with the HLA-A03 supertype. Three peptides had been identified with high binding scores for HLA-A03 supertypes using bioinformatic algorhythms, high measured binding affinity for HLA-A03 supertype molecules, and ability to elicit IFN-γ production by human HLA-A03 supertype peripheral blood CD8+ T cells from seropositive but not seronegative persons.
Results
Herein, when these peptides were administered with the universal CD4+T cell epitope PADRE (AKFVAAWTLKAAA) and formulated as lipopeptides, or administered with GLA-SE either alone, or with Pam2Cys added, we found we successfully created preparations that induced IFN-γ and reduced parasite burden in HLA-A*1101(an HLA-A03 supertype allele) transgenic mice. GLA-SE is a novel emulsified synthetic TLR4 ligand that is known to facilitate development of T Helper 1 cell (TH1) responses. Then, so our peptides would include those expressed in tachyzoites, bradyzoites and sporozoites from both Type I and II parasites, we used our approaches which had identified the initial peptides. We identified additional peptides using bioinformatics, binding affinity assays, and study of responses of HLA-A03 human cells. Lastly, we found that immunization of HLA-A*1101 transgenic mice with all the pooled peptides administered with PADRE, GLA-SE, and Pam2Cys is an effective way to elicit IFN-γ producing CD8+ splenic T cells and protection. Immunizations included the following peptides together: KSFKDILPK (SAG1224-232); AMLTAFFLR (GRA6164-172); RSFKDLLKK (GRA7134-142); STFWPCLLR (SAG2C13-21); SSAYVFSVK(SPA250-258); and AVVSLLRLLK(SPA89-98). This immunization elicited robust protection, measured as reduced parasite burden using a luciferase transfected parasite, luciferin, this novel, HLA transgenic mouse model, and imaging with a Xenogen camera.
Conclusions
Toxoplasma gondii peptides elicit HLA-A03 restricted, IFN-γ producing, CD8+ T cells in humans and mice. These peptides administered with adjuvants reduce parasite burden in HLA-A*1101 transgenic mice. This work provides a foundation for immunosense based vaccines. It also defines novel adjuvants for newly identified peptides for vaccines to prevent toxoplasmosis in those with HLA-A03 supertype alleles.
doi:10.1186/1745-7580-6-12
PMCID: PMC3009956  PMID: 21129215
20.  HLA-associated susceptibility to childhood B-cell precursor ALL: definition and role of HLA-DPB1 supertypes 
British Journal of Cancer  2008;98(6):1125-1131.
Childhood B-cell precursor (BCP) ALL is thought to be caused by a delayed immune response to an unidentified postnatal infection. An association between BCP ALL and HLA class II (DR, DQ, DP) alleles could provide further clues to the identity of the infection, since HLA molecules exhibit allotype-restricted binding of infection-derived antigenic peptides. We clustered >30 HLA-DPB1 alleles into six predicted peptide-binding supertypes (DP1, 2, 3, 4, 6, and 8), based on amino acid di-morphisms at positions 11 (G/L), 69 (E/K), and 84 (G/D) of the DPβ1 domain. We found that the DPβ11-69-84 supertype GEG (DP2), was 70% more frequent in BCP ALL (n=687; P<10−4), and 98% more frequent in cases diagnosed between 3 and 6 years (P<10−4), but not <3 or >6 years, than in controls. Only one of 21 possible DPB1 supergenotypes, GEG/GKG (DP2/DP4) was significantly more frequent in BCP ALL (P=0.00004) than controls. These results suggest that susceptibility to BCP ALL is associated with the DP2 supertype, which is predicted to bind peptides with positively charged, nonpolar aromatic residues at the P4 position, and hydrophobic residues at the P1 and P6 positions. Studies of peptide binding by DP2 alleles could help to identify infection(s) carrying these peptides.
doi:10.1038/sj.bjc.6604257
PMCID: PMC2275491  PMID: 18334973
HLA-DPB1; supertypes; BCP ALL; case–control comparison; allele frequency; peptide-binding pockets
21.  The most common Chinese rhesus macaque MHC class I molecule shares peptide binding repertoire with the HLA-B7 supertype 
Immunogenetics  2010;62(7):451-464.
Of the two rhesus macaque subspecies used for AIDS studies, the Simian immunodeficiency virus-infected Indian rhesus macaque (Macaca mulatta) is the most established model of HIV infection, providing both insight into pathogenesis and a system for testing novel vaccines. Despite the Chinese rhesus macaque potentially being a more relevant model for AIDS outcomes than the Indian rhesus macaque, the Chinese-origin rhesus macaques have not been well-characterized for their major histocompatibility complex (MHC) composition and function, reducing their greater utilization. In this study, we characterized a total of 50 unique Chinese rhesus macaques from several varying origins for their entire MHC class I allele composition and identified a total of 58 unique complete MHC class I sequences. Only nine of the sequences had been associated with Indian rhesus macaques, and 28/58 (48.3%) of the sequences identified were novel. From all MHC alleles detected, we prioritized Mamu-A1*02201 for functional characterization based on its higher frequency of expression. Upon the development of MHC/peptide binding assays and definition of its associated motif, we revealed that this allele shares peptide binding characteristics with the HLA-B7 supertype, the most frequent supertype in human populations. These studies provide the first functional characterization of an MHC class I molecule in the context of Chinese rhesus macaques and the first instance of HLA-B7 analogy for rhesus macaques.
Electronic supplementary material
The online version of this article (doi:10.1007/s00251-010-0450-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s00251-010-0450-3
PMCID: PMC2890073  PMID: 20480161
Rhesus macaque; MHC; HLA; CTL
22.  Contribution of immunological and virological factors to extremely severe primary HIV-1 infection 
Background
During acute HIV infection, high viral loads and the induction of host immune responses typically coincide with the onset of clinical symptoms. However, clinically severe presentations during acute HIV-1 infection, including AIDS-defining symptoms, are unusual.
Methods
Virus isolates were tested for clade, drug susceptibility, coreceptor usage, and growth rate for two cases of clinically severe sexual transmission. HLA genotype was determined, and HIV-1-specific CTL responses to an overlapping peptide set spanning the entire HIV clade A and clade B proteome were assayed.
Results
The virus isolated from the two unrelated cases of severe primary HIV-1 infection showed R5/X4 dual/mixed tropism, belonged to clade B and CRF02-AG, and were highly replicative in peripheral blood mononuclear cell culture. Impaired humoral responses were paralleled by a profound absence of HIV-1-specific CTL responses to the entire viral proteome in the two study cases. One case for which the virus source was available, showed a remarkable HLA similarity between the transmission pair as all 4 HLA-A and -B alleles were HLA supertype-matched between the subjects involved in the transmission case.
Conclusions
The data suggest that concurrence of viral and host factors contribute to the clinical severity of primary HIV-1 infection and that subjects infected with highly replicative dual tropic viruses are more prone to develop AIDS-defining symptoms during acute infection if they are unable to mount humoral and cellular HIV-1-specific immune responses. Concordant HLA supertypes might facilitate the preferential transmission of HLA-adapted viral variants, further accelerating disease progression.
doi:10.1086/595704
PMCID: PMC2806184  PMID: 19093810
primary HIV-1 infection; HLA supertypes; CTL responses; R5/X4 dual tropism; rapid disease progression
23.  Identification of immunogenic HLA-B7 “Achilles' heel” epitopes within highly conserved regions of HIV 
Vaccine  2007;26(24):3059-3071.
Summary
Genetic polymorphisms in class I human leukocyte antigen molecules (HLA) have been shown to determine susceptibility to HIV infection as well as the rate of progression to AIDS. In particular, the HLA-B7 supertype has been shown to be associated with high viral loads and rapid progression to disease. Using a multiplatform in silico/in vitro approach, we have prospectively identified 45 highly conserved, putative HLA-B7 restricted HIV CTL epitopes and evaluated them in HLA binding and ELISpot assays. All 45 epitopes (100%) bound to HLA-B7 in cell-based HLA binding assays: 28 (62%) bound with high affinity, 6 (13%) peptides bound with medium affinity and 11 (24%) bound with low affinity. Forty of the 45 peptides (88%) stimulated a IFN-γ response in PBMC from at least one subject. Eighteen of these 40 epitopes have not been previously described; an additional eight epitopes have not been previously described as restricted by B7. The HLA-B7 restricted epitopes discovered using this in silico screening approach are highly conserved across strains and clades of HIV as well as conserved in the HIV genome over the 20 years since HIV-1 isolates were first sequenced. This study demonstrates that it is possible to select a broad range of HLA-B7 restricted epitopes that comprise stable elements in the rapidly mutating HIV genome. The most immunogenic of these epitopes will be included in the GAIA multi-epitope vaccine.
doi:10.1016/j.vaccine.2007.12.004
PMCID: PMC2553891  PMID: 18206276
T cell epitope; HIV; HLA-B7; Vaccine
24.  HLA Class I Supertypes in Type 1 Diabetic Children in an Urban Children’s Hospital 
Type 1 diabetes is an autoimmune disorder characterized by progressive destruction of insulin secreting β cells of the pancreas, in which CD8+ T cells play a critical role. The diversity in the HLA alleles expressed among various racial and ethnic groups leads to great variability in antigen presentation and recognition by CD8+ T cells in the context of MHC class I molecules. To date, studies aimed at identifying disease relevant antigenic epitopes have focused on using mice transgenic for HLA-A*0201, a common allele, particularly among Caucasians. We present HLA class I typing data from 88 type 1 diabetic children at the Children’s Hospital at Montefiore, where the patient population is ethnically diverse but largely minority. When categorized into the HLA supertypes A2, A3, B7, and C1, 77% of those studied belong to at least 1 supertype, and of these, 65% do not belong to the A2 supertype, which is the supertype represented by the HLA-A*0201 allele. These results support the need for studies using HLA transgenic mice expressing MHC molecules representative of a variety of HLA supertypes, particularly when searching for antigenic epitopes applicable for study among largely urban, minority pediatric populations.
doi:10.1196/annals.1447.005
PMCID: PMC2738637  PMID: 19120273
Type 1 Diabetes; Human Leukocyte Antigen (HLA); Transgenic Mice
25.  Human histocompatibility leukocyte antigen-binding supermotifs predict broadly cross-reactive cytotoxic T lymphocyte responses in patients with acute hepatitis. 
Journal of Clinical Investigation  1997;100(3):503-513.
The present study was designed to determine if highly conserved hepatitis B virus (HBV)-derived peptides that bind multiple HLA class I alleles with high affinity are recognized as cytotoxic T lymphocyte (CTL) epitopes in acutely infected patients. Peripheral blood mononuclear cells from 67 patients with acute hepatitis B, and 12 patients convalescent from acute hepatitis B, were stimulated with three panels of peptides, each of which bind with high affinity to several class I alleles from the HLA-A2-, HLA-A3-, or HLA-B7-supertypes. In these patients, 8 of the 19 peptides tested were found to represent CTL epitopes recognized by two or more alleles in each supertype. Two sets of nested peptides were recognized in the context of alleles with completely unrelated peptide binding specificities. Finally, promiscuous recognition by the same CTL of a given peptide presented by target cells expressing different A2 subtypes was also commonly observed. In conclusion, several HBV-specific CTL epitopes, recognized by acutely infected or convalescent patients in the context of a wide range of HLA alleles have been identified. These results demonstrate the functional relevance of the supertype grouping of HLA class I molecules in a human viral disease setting. Furthermore, they represent a significant advance in the development of a totally synthetic vaccine to terminate chronic HBV infection and support the feasibility of a systematic approach to development of similar vaccines for prevention and treatment of other chronic viral infections.
PMCID: PMC508216  PMID: 9239396

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