Allele polymorphism and haplotype diversity of HLA-A, -B and -DRB1 loci in sequence-based typing for Chinese Uyghur ethnic group

Background

Previous studies indicate that the frequency distributions of HLA alleles and haplotypes vary from one ethnic group to another or between the members of the same ethnic group living in different geographic areas. It is necessary and meaningful to study the high-resolution allelic and haplotypic distributions of HLA loci in different groups.

Methodology/Principal Findings

High-resolution HLA typing for the Uyghur ethnic minority group using polymerase chain reaction-sequence-based-typing method was first reported. HLA-A, -B and -DRB1 allelic distributions were determined in 104 unrelated healthy Uyghur individuals and haplotypic frequencies and linkage disequilibrium parameters for HLA loci were estimated using the maximum-likelihood method. A total of 35 HLA-A, 51 HLA-B and 33 HLA-DRB1 alleles were identified at the four-digit level in the population. High frequency alleles were HLA-A*1101 (13.46%), A*0201 (12.50%), A*0301 (10.10%); HLA-B*5101(8.17%), B*3501(6.73%), B*5001 (6.25%); HLA-DRB1*0701 (16.35%), DRB1*1501 (8.65%) and DRB1*0301 (7.69%). The two-locus haplotypes at the highest frequency were HLA-A*3001-B*1302 (2.88%), A*2402-B*5101 (2.86%); HLA-B*5001-DRB1*0701 (4.14%) and B*0702-DRB1*1501 (3.37%). The three-locus haplotype at the highest frequency was HLA-A*3001-B*1302-DRB1*0701(2.40%). Significantly high linkage disequilibrium was observed in six two-locus haplotypes, with their corresponding relative linkage disequilibrium parameters equal to 1. Neighbor-joining phylogenetic tree between the Uyghur group and other previously reported populations was constructed on the basis of standard genetic distances among the populations calculated using the four-digit sequence-level allelic frequencies at HLA-A, HLA-B and HLA-DRB1 loci. The phylogenetic analyses reveal that the Uyghur group belongs to the northwestern Chinese populations and is most closely related to the Xibe group, and then to Kirgiz, Hui, Mongolian and Northern Han.

Conclusions/Significance

The present findings could be useful to elucidate the genetic background of the population and to provide valuable data for HLA matching in clinical bone marrow transplantation, HLA-linked disease-association studies, population genetics, human identification and paternity tests in forensic sciences.     

Frequency of HLA-A*03 associates with HIV-1 infection in a Chinese cohort

During the early mid-1990s, a number of rural farmers across central China were employed to the unregulated plasmaselling-activity and many of them were infected by HIV-1. However, AIDS progression in the former blood donors (FBDs) is various. The aim of this study is to assess human leukocyte antigen (HLA) class I allele distribution in FBDs and evaluate its association with HIV-1 infection and disease progression. A total of 353 FBDs were enrolled in the cohort including 294 ART naïve HIV-1 seropositive and 59 HIV-1 seronegative age-matched subjects. The viral load and CD4/CD8 T cell counts were assessed in all subjects. Compared with HIV-seropositive group, the frequency of HLA-A*03 in control was significantly higher. After classifying the HLA-B alleles of the subjects according to the presence of Bw4/Bw6 serological epitopes, detrimental effect of HLA Bw6/ Bw6 homozygosity was also confirmed in the HIV-seropositive subjects. This study provides novel evidence on HLA class I allele distribution and association of HLA-A*03 frequency with HIV-1 infection and viremia in the HIV-1 infected FBDs, which may throw light on intervention strategy for the HIV-1 infection and our understanding how host immunity and genetic background affect HIV infection and AIDS progression.     

Survival and HLA-B*57 in HIV/HCV Co-Infected Patients on Highly Active Antiretroviral Therapy (HAART)

Background and aims

HLA class I alleles, in particular HLA-B*57, constitute the most consistent host factor determining outcomes in untreated HCV- and HIV-infection. In this prospective cohort study, we analysed the impact of HLA class I alleles on all-cause mortality in patients with HIV-, HCV- and HIV/HCV- co-infection receiving HAART.

Methods

In 2003 HLA-A and B alleles were determined and patients were prospectively followed in 3-month intervals until 2013 or death. HLA-A and B alleles were determined by strand-specific oligonucleotide hybridisation and PCR in 468 Caucasian patients with HCV- (n=120), HIV- (n=186) and HIV/HCV-infection (n=162). All patients with HIV-infection were on HAART. In each patient group, HLA class I-associated survival was analysed by Kaplan-Meier method and Cox regression analysis.

Results

At recruitment the proportion of patients carrying a HLA-B*57 allele differed between HIV- (12.9%) and HCV-infection (4.2%). Kaplan Meier analysis revealed significantly increased mortality in HLA-B*57-positive patients with HIV-infection (p=0.032) and HIV/HCV-co-infection (p=0.004), which was apparently linked to non-viral infections. Cox logistic regression analysis confirmed HLA-B*57 (p=0.001), serum gamma-glutamyltranspeptidase (p=0.003), serum bilirubin (p=0.022) and CD4 counts (p=0.041) as independent predictors of death in HIV-infected patients.

Conclusion

Differences in the prevalence of HLA-B*57 at study entry between HIV- and HCV- infected patients may reflect immune selection in the absence of antiviral therapy. When patients were treated with HAART, however, HLA-B*57 was associated with increased mortality and risk to die from bacterial infections and sepsis, suggesting an ambiguous role of HLA-B*57 for survival in HIV/HCV infection depending on the circumstances.     

Polymorphic sites away from the Bw4 epitope that affect interaction of Bw4+ HLA-B with KIR3DL1

KIR3DL1 is a polymorphic, inhibitory NK cell receptor specific for the Bw4 epitope carried by subsets of HLA-A and HLA-B allotypes. The Bw4 epitope of HLA-B*5101 and HLA-B*1513 is determined by the NIALR sequence motif at positions 77, 80, 81, 82, and 83 in the alpha(1) helix. Mutation of these positions to the residues present in the alternative and nonfunctional Bw6 motif showed that the functional activity of the Bw4 epitopes of B*5101 and B*1513 is retained after substitution at positions 77, 80, and 81, but lost after substitution of position 83. Mutation of leucine to arginine at position 82 led to loss of function for B*5101 but not for B*1513. Further mutagenesis, in which B*1513 residues were replaced by their B*5101 counterparts, showed that polymorphisms in all three extracellular domains contribute to this functional difference. Prominent were positions 67 in the alpha(1) domain, 116 in the alpha(2) domain, and 194 in the alpha(3) domain. Lesser contributions were made by additional positions in the alpha(2) domain. These positions are not part of the Bw4 epitope and include residues shaping the B and F pockets that determine the sequence and conformation of the peptides bound by HLA class I molecules. This analysis shows how polymorphism at sites throughout the HLA class I molecule can influence the interaction of the Bw4 epitope with KIR3DL1. This influence is likely mediated by changes in the peptides bound, which alter the conformation of the Bw4 epitope.     

HLA Class I and Class II Associations with ESRD in Saudi Arabian Population

Background

Chronic renal failure (CRF) leads in the majority of instances to end stage renal disease (ESRD) requiring renal replacement therapy. Our interest was to evaluate the possible associations of HLA class I and class II antigens with ESRD independent of other factors, in Saudi Arabia population.

Methodology

A retrospective study to determine the HLA class I and class II polymorphisms and their association with ESRD, was performed on 350 patients with ESRD, and 105 healthy unrelated control. Patients and control groups were typed by SSOP lumenix techniques. The alleles positively associated to the ESRD were: HLA-B*15, B*18, B*49 - DRB1*03, negatively associated alleles were A*26, HLA-B*39, B*50. The haplotypes positively associated with ESRD were: HLA-A*01-DRB1*13 and HLA-A*30-DRBI*03. The negatively associated haplotypes were: HLA-A*02-B*39, A*02-B*50, A*24-B*35, A*24-B*58, A*24-DRB1*16, A*68-DRB1*04, A*02-DQB1*03, A*29-DQB1*02, A*29-DOB1*05 and B*27-DRB1*07 and the last one is the most significant protective haplotypes.

Conclusion

The high Relative Risk (RR) observed and its statistical correlation reflect the strength of the described association between HLA antigens and ESRD.     

Co-Operative Additive Effects between HLA Alleles in Control of HIV-1

Background

HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appear to function co-operatively to result in greater immune control of HIV than mediated by either single allele alone. We here investigate the extent to which HLA alleles - irrespective of linkage disequilibrium - function co-operatively.

Methodology/Principal Findings

We here refined a computational approach to the analysis of >2000 subjects infected with C-clade HIV first to discern the individual effect of each allele on disease control, and second to identify pairs of alleles that mediate ‘co-operative additive’ effects, either to improve disease suppression or to contribute to immunological failure. We identified six pairs of HLA class I alleles that have a co-operative additive effect in mediating HIV disease control and four hazardous pairs of alleles that, occurring together, are predictive of worse disease outcomes (q<0.05 in each case). We developed a novel ‘sharing score’ to quantify the breadth of CD8+ T cell responses made by pairs of HLA alleles across the HIV proteome, and used this to demonstrate that successful viraemic suppression correlates with breadth of unique CD8+ T cell responses (p = 0.03).

Conclusions/Significance

These results identify co-operative effects between HLA Class I alleles in the control of HIV-1 in an extended Southern African cohort, and underline complementarity and breadth of the CD8+ T cell targeting as one potential mechanism for this effect.     

Beh?et’s disease in HLA-B*51 negative Germans and Turks shows association with HLA-Bw4-80I

Introduction

Behçet’s disease (BD) as systemic vasculitis of unknown etiology is associated with HLA-B*51 in European and Asian populations. HLA-A*26 was claimed as an additional BD susceptibility marker in Japanese and Greek patients. This study was performed to test for HLA associations in HLA-B*51 negative German and Turkish BD populations.

Methods

In total, 65 German and 46 Turkish patients lacking HLA-B*51 were analyzed in comparison to healthy HLA-B*51 negative Germans (n = 1500) and Turks (n = 130). HLA-A/B genotypes were determined by SSOP. P-values with correction for multiple testing (p_c), χ2-test and odds ratio (OR) were used for statistical evaluation.

Results

HLA-A*26 was significantly more frequent in HLA-B*51⁻ German patients [p_c = 0.0076, OR = 3.23, 95% CI 1.63 to 6.39] than in respective controls. HLA-A*26 was also elevated in a smaller group of Turkish patients versus the controls. Significant association of HLA-Bw4 with isoleucine at amino-acid position 80 (HLA-Bw4-80I) was found in the HLA-B*51⁻ German cohort of BD patients [p_c = 0.0042, OR = 2.35, 95% CI 1.41 to 3.93) and in the Turkish patients in comparison to the respective controls [p = 0.025, OR = 2.17, 95% CI 1.09 to 4.31]. On the contrary, HLA-Bw4-80 T was reduced in both HLA-B*51⁻ BD patient cohorts.

Conclusions

The study shows a significant association of HLA-Bw4-80I present on HLA-B*51 as well as on other B-locus molecules with BD. This indicates that distinctive Bw4 epitopes on HLA-B locus molecules could play a role in BD pathogenesis. The study also indicates an association with HLA-A*26 in German and Turkish BD patients as a genetic risk factor independent of HLA-B*51.     

Resistance-associated epitopes of HIV-1C—highly probable candidates for a multi-epitope vaccine

Earlier studies have identified a large number of immunogenic epitopes in HIV-1. Efforts are required to prioritize these epitopes in order to identify the best candidates for formulating an effective multi-epitope vaccine for HIV. We modeled 155 known cytotoxic T lymphocyte epitopes of HIV-1 subtype C on the 3D structure of HLA-A*0201, HLA-B*2705, and HLA-B*5101 using MODPROPEP, as these alleles are known to be associated with resistance to HIV/slow progression to AIDS. Thirty-six epitopes were identified to bind to all the three HLA alleles with better binding affinity than the control peptides complexed with each HLA allele but not to any of the HLA alleles reported to be associated with susceptibility to HIV infection/rapid progression to disease. As increase in stability of the epitope-HLA complex results in increased immunogenicity, the short-listed epitopes could be suitable candidates for vaccine development. Twenty of the 36 epitopes were polyfunctional in nature adding to their immunological relevance for vaccine design. Further, 9 of the 20 polyfunctional epitopes were found to bind to all three resistance-associated HLA alleles using an additional method, adding worth to their potential as candidates for a vaccine formulation for HIV-1C.     

Cutting Edge: Allele-specific and peptide-dependent interactions between KIR3DL1 and HLA-A and HLA-B

Although it is clear that KIR3DL1 recognizes Bw4(+) HLA-B, the role of Bw4(+) HLA-A allotypes as KIR3DL1 ligands is controversial. We therefore examined the binding of tetrameric HLA-A and -B complexes, including HLA*2402, a common Bw4(+) HLA-A allotype, to KIR3DL1*001, *005, *007, and *1502 allotypes. Only Bw4(+) tetramers bound KIR3DL1. Three of four HLA-A*2402 tetramers bound one or more KIR3DL1 allotypes and all four KIR3DL1 allotypes bound to one or more HLA-A*2402 tetramers, but with different binding specificities. Only KIR3DL1*005 bound both HLA-A*2402 and HLA-B*5703 tetramers. HLA-A*2402-expressing target cells were resistant to lysis by NK cells expressing KIR3DL1*001 or *005. This study shows that HLA-A*2402 is a ligand for KIR3DL1 and demonstrates how the binding of KIR3DL1 to Bw4(+) ligands depends upon the bound peptide as well as HLA and KIR3DL1 polymorphism.     

中国汉族个体HLA-A、-B基因全长序列的测定及调控区多态性

文章利用20个中国汉族个体样本建立了稳定精确的HLA-A、-B基因全长序列的克隆测序方法, 获得HLA-A 10个等位基因4.2 kb序列, HLA-B 6个等位基因3.7 kb序列, 序列涵盖了两个基因的所有外显子、所有内含子、5′启动子区以及3′非翻译区(3′UTR)。A*1153是文章发现的一个新等位基因, B*151101的内含子序列、5个HLA-A以及2个HLA-B等位基因的5′启动子序列和3′UTR序列为国际上首次报道, 其他等位基因均延伸了IMGT/HLA数据库中释放的全长序列。文章首次在中国汉族个体中测定了IMGT/HLA数据库中没有覆盖的HLA-A、-B基因的上游5′启动子以及下游3′UTR区域的多态性模式。HLA-A基因5′启动子延伸区域共发现26个SNPs和一处3 bp(AAA/-)的插入/缺失, 3′UTR延伸区域共发现14个SNPs; HLA-B基因5′启动子延伸区域共发现5个SNPs和一处1 bp(T/-)的插入/缺失, 3′UTR延伸区域共发现8个SNPs。通过对两个基因的5′启动子、外显子以及3′UTR的系统发育树分析, 发现两个基因调控区与外显子的进化关系有所不同, HLA-A基因除A*24020101外, 其他等位基因两端调控区与外显子连锁比较紧密, HLA-B基因两端调控区与外显子之间则发生了较为频繁的重组事件。     

Association and differentiation of MHC class I and II polymorphic Alu insertions and HLA-A, -B, -C and -DRB1 alleles in the Chinese Han population

In order to investigate the polymorphism of Alu insertions (POALINs) in the HLA region, we genotyped ten Alu loci (AluMICB, AluTF, AluHJ, AluHG, AluHF in the HLA class I region and AluDPB2, AluDQA2, AluDQA1, AluDRB1, AluORF10 in the HLA class II region) to determine their allele frequencies and associations with the HLA-A, HLA-B, HLA-C and HLA-DRB1 genes in the Chinese Han population. Our results showed the ten-loci POALINs varied in frequency between 0.003 and 0.425. By comparing the data of the ten-loci POALIN in Chinese Han with Japanese and Caucasian data, marked differences were observed between the three ethnic groups at the allelic or haplotypic levels. Each POALIN was in significant linkage disequilibrium with a variety of HLA-A, -B, -C and -DRB1 alleles, and was associated with a variety of HLA-A, -B, -C and -DRB1 allele in Chinese Han. This comparative study of multilocus POALINs in the HLA class I and II regions of the Chinese Han population shows that POALINs alone or as haplotypes together with the HLA class I and II alleles are informative genetic markers for the identification of HLA class I and II allele and variations, such as crossing over events within the same and/or different populations.     

HIV Control through a Single Nucleotide on the HLA-B Locus

Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, identifying the exact mechanism involved is complicated by several factors. HLA-Bw4 alleles provide ligands for NK cells and for CD8 T cells, and strong linkage disequilibrium between HLA class I alleles complicates the discrimination of individual HLA allelic effects from those of other HLA and non-HLA alleles on the same haplotype. Here, we exploit an experiment of nature involving two recently diverged HLA alleles, HLA-B*42:01 and HLA-B*42:02, which differ by only a single amino acid. Crucially, they occur primarily on identical HLA class I haplotypes and, as Bw6 alleles, do not act as NK cell ligands and are therefore largely unconfounded by other genetic factors. We show that in an outbred cohort (n = 2,093) of HIV C-clade-infected individuals, a single amino acid change at position 9 of the HLA-B molecule critically affects peptide binding and significantly alters the cytotoxic T lymphocyte (CTL) epitopes targeted, measured directly ex vivo by gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay (P = 2 × 10⁻¹⁰) and functionally through CTL escape mutation (P = 2 × 10⁻⁸). HLA-B*42:01, which presents multiple Gag epitopes, is associated with a 0.52 log₁₀ lower viral-load set point than HLA-B*42:02 (P = 0.02), which presents no p24 Gag epitopes. The magnitude of this effect from a single amino acid difference in the HLA-A*30:01/B*42/Cw*17:01 haplotype is equivalent to 75% of that of HLA-B*57:03, the most protective HLA class I allele in this population. This naturally controlled experiment represents perhaps the clearest demonstration of the direct impact of a particular HIV-specific CTL on disease control.     

HLA antibody responses in HLA class I transgenic mice

In a previous report we described how cross-immunizations of pairs of transgenic mice expressing different HLA class I antigens led to the production of antibodies directed exclusively at polymorphic epitopes. This was ascribed to self-tolerance of HLA that prevents immune responses to monomorphic epitopes and focuses responses on polymorphic ones. In the present report we extend our findings and demonstrate that immunizations of class I transgenic mice with HLA transfected mouse fibrosarcoma as well as with human lymphoblastoid cells also preferentially yield antibodies to polymorphic epitopes. This was the case whether or not immunizations were carried out across locus barriers [e.g., Tg (HLA-A *0201) or Tg (HLA-Cw*0301) transgenic mice immunized with HLA-B27 transfectants] or within the same locus [e.g., Tg (HLA-B*1302) transgenic mice immunized with HLA-B27 transfectants or B27-expressing lympho-blastoid cell]. Use of an extended immunization protocol with four or more booster injections favored antibodies of IgG isotype with affinities high enough to lyse normal peripheral blood lymphocytes (PBLs) in complement-dependent cytotoxicity assays and to immunoprecipitate HLA antigens. The specificities covered by the monoclonal antibodies (mAbs) could be either broad or narrow, depending on the genetic distance of the HLA antigens or alleles involved. For instance, a Tg(HLA-B*1302) transgenic mouse immunized with B27 produced both broad B7/B27-specific antibodies, Bw4-specific antibodies, and one antibody reacting with all B alleles except B13 and with some C alleles. On the other hand, a Tg(HLA-B*1302) transgenic mouse immunized with Bw47 transfectants responded narrowly with an antibody to Bw60 and Bw47. Thus it appears that by choosing appropriate recipient mice and closely related or more distant HLA antigens, antibodies of a programmed specificity can be generated. Address correspondence and offprint requests to: U. Hämmerling.     

Cutting Edge: Epitope-dependent effect of Nef-mediated HLA class I down-regulation on ability of HIV-1-specific CTLs to suppress HIV-1 replication

It is believed that Nef-mediated HLA class I down-regulation is one of the mechanisms that allow HIV-1-infected cells to escape from being killed by HIV-1-specific human CTLs. In this study, we show that the effect of Nef-mediated HLA class I down-regulation on the ability of HIV-1-specific CTLs to suppress HIV-1 replication is epitope dependent. The CTLs specific for two Pol epitopes presented by HLA-B*5101, one of the HLA alleles associated with slow progression to AIDS, effectively killed HIV-1-infected CD4+ T cells and suppressed HIV-1 replication. In contrast, those specific for the other four epitopes failed to kill HIV-1-infected CD4+ T cells and partially or hardly suppressed HIV-1 replication. The difference of the ability between these two types of CTLs may result from the difference of the number of HLA class I epitope complex on the surface of NL-432-infected CD4+ T cells.     

An Analysis of HLA-A, -B,and -DRB1 Allele and Haplotype Frequencies of 21,918 Residents Living in Liaoning,China

HLA-A, -B and -DRB1 allele frequencies and their haplotype frequencies in 21,918 Chinese residents living in Liaoning Province, who were registered as volunteer donors of China Marrow Donor Registry, were investigated. They are composed of 93.37% Han Chinese, 5.1% Manchus, 0.57% Mongols, 0.46% Hui persons, 0.29% Koreans and 0.14% Xibe ethnic group. In total eighteen different HLA-A alleles, forty-eight different HLA-B alleles and fourteen different HLA-DRB1 alleles have been identified. Their frequencies are in agreement with the Hardy-Weinberg equilibrium. For Han Chinese in Liaoning, 1,534 different HLA-A-B-DRB1 haplotypes were identified, with a frequency of higher than 0.01%. A*30-B*13-DRB1*07, A*02-B*46-DRB1*09 and A*02-B*13-DRB1*12 are the most frequent haplotypes among Liaoning Han. While Liaoning Han, Liaoning Manchu, Liaoning Mongol, Liaoning Hui and Liaoning Korean share the northern Han characteristic haplotypes, all minority ethnic groups with the exception of Liaoning Manchu have developed their own unique HLA profiles. This dataset characterizes the HLA allele and haplotype frequencies in the Liaoning area and suggests that it is different from those in other parts of China and ethnic groups, which implicates transplant donor searching strategies and studies on population genetics.     

中国新疆维族人群HLA-B等位基因与HIV-1感染易感性或抗性

通过对中国维吾尔族人群HLA-B等位基因的分布频率的研究,探讨HLA-B等位基因与HIV感染的易感 或抵抗性的相关性。本研究用PCR-SSP的方法对新疆维吾尔族110例无相关的健康对照者(HIV阴性)和128例 HIV阳性感染者进行HLA-B等位基因分型。用POPGEN软件对健康对照者人群进行Hardy-Weinberg平衡检 测,用卡方检验分析HLA-B等位基因在健康对照者和HIV阳性感染者频率分布的差异。在HIV-1阳性感染者 中,B*4901等位基因频率显著性增加(B*4901:P=0．02．OR=3．06,95%CI=1．16～8．10)。而在健埭对照者 中,B*40等位基因顿率增加具有统计意义(B*40:P=0．02．OR=0．39．95％CI=0．07～0．92)。由此可见,B* 4901等位基因可能与HIV-1感染的易感性有关,而B*40等位基因可能与与HIV-1感染的抵抗性有关。     

HLA-A*7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B*5703

The potential contribution of HLA-A alleles to viremic control in chronic HIV type 1 (HIV-1) infection has been relatively understudied compared with HLA-B. In these studies, we show that HLA-A*7401 is associated with favorable viremic control in extended southern African cohorts of >2100 C-clade-infected subjects. We present evidence that HLA-A*7401 operates an effect that is independent of HLA-B*5703, with which it is in linkage disequilibrium in some populations, to mediate lowered viremia. We describe a novel statistical approach to detecting additive effects between class I alleles in control of HIV-1 disease, highlighting improved viremic control in subjects with HLA-A*7401 combined with HLA-B*57. In common with HLA-B alleles that are associated with effective control of viremia, HLA-A*7401 presents highly targeted epitopes in several proteins, including Gag, Pol, Rev, and Nef, of which the Gag epitopes appear immunodominant. We identify eight novel putative HLA-A*7401-restricted epitopes, of which three have been defined to the optimal epitope. In common with HLA-B alleles linked with slow progression, viremic control through an HLA-A*7401-restricted response appears to be associated with the selection of escape mutants within Gag epitopes that reduce viral replicative capacity. These studies highlight the potentially important contribution of an HLA-A allele to immune control of HIV infection, which may have been concealed by a stronger effect mediated by an HLA-B allele with which it is in linkage disequilibrium. In addition, these studies identify a factor contributing to different HIV disease outcomes in individuals expressing HLA-B*5703.     

Preferential HLA usage in the influenza virus-specific CTL response

To study whether individual HLA class I alleles are used preferentially or equally in human virus-specific CTL responses, the contribution of individual HLA-A and -B alleles to the human influenza virus-specific CTL response was investigated. To this end, PBMC were obtained from three groups of HLA-A and -B identical blood donors and stimulated with influenza virus. In the virus-specific CD8(+) T cell population, the proportion of IFN-gamma- and TNF-alpha-producing cells, restricted by individual HLA-A and -B alleles, was determined using virus-infected C1R cells expressing a single HLA-A or -B allele for restimulation of these cells. In HLA-B*2705- and HLA-B*3501-positive individuals, these alleles were preferentially used in the influenza A virus-specific CTL response, while the contribution of HLA-B*0801 and HLA-A*0101 was minor in these donors. The magnitude of the HLA-B*0801-restricted response was even lower in the presence of HLA-B*2705. C1R cells expressing HLA-B*2705, HLA-A*0101, or HLA-A*0201 were preferentially lysed by virus-specific CD8(+) T cells. In contrast, the CTL response to influenza B virus was mainly directed toward HLA-B*0801-restricted epitopes. Thus, the preferential use of HLA alleles depended on the virus studied.     

HLA and non-HLA genes in Beh?et’s disease: a multicentric study in the Spanish population

Introduction

According to genome wide association (GWA) studies as well as candidate gene approaches, Behçet’s disease (BD) is associated with human leukocyte antigen (HLA)-A and HLA-B gene regions. The HLA-B51 has been consistently associated with the disease, but the role of other HLA class I molecules remains controversial. Recently, variants in non-HLA genes have also been associated with BD. The aims of this study were to further investigate the influence of the HLA region in BD and to explore the relationship with non-HLA genes recently described to be associated in other populations.

Methods

This study included 304 BD patients and 313 ethnically matched controls. HLA-A and HLA-B low resolution typing was carried out by PCR-SSOP Luminex. Eleven tag single nucleotide polymorphisms (SNPs) located outside of the HLA-region, previously described associated with the disease in GWA studies and having a minor allele frequency in Caucasians greater than 0.15 were genotyped using TaqMan assays. Phenotypic and genotypic frequencies were estimated by direct counting and distributions were compared using the χ² test.

Results

In addition to HLA-B*51, HLA-B*57 was found as a risk factor in BD, whereas, B*35 was found to be protective. Other HLA-A and B specificities were suggestive of association with the disease as risk (A*02 and A*24) or protective factors (A*03 and B*58). Regarding the non-HLA genes, the three SNPs located in IL23R and one of the SNPs in IL10 were found to be significantly associated with susceptibility to BD in our population.

Conclusion

Different HLA specificities are associated with Behçet’s disease in addition to B*51. Other non-HLA genes, such as IL23R and IL-10, play a role in the susceptibility to the disease.     

HLA Class I-Mediated Control of HIV-1 in the Japanese Population, in Which the Protective HLA-B*57 and HLA-B*27 Alleles Are Absent

We investigated the effect of HLA class I alleles on clinical parameters for HIV-1 disease progression in the Japanese population, where two strongly protective alleles, HLA-B*57 and HLA-B*27, are virtually nonexistent. HLA-B alleles showed a dominant role, primarily through HLA-B*67:01 and the HLA-B*52:01-C*12:02 haplotype. Neither a rare-allele nor a heterozygote advantage was found, suggesting that the effect of HLA alleles in the Japanese population is either different from those observed in Africans and Caucasians or undetectable due to limited power.