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Peptide binding specificities of HLA-B*5701 and B*5801
YaLan Zhang,Hu Mei,Qing Wang,JiangAn Xie,Juan Lv,XianChao Pan,Wen Tan
Science China Life Sciences , 2012, DOI: 10.1007/s11427-012-4374-z
Abstract: Recently, genome wide association studies showed that there is a strong association between abacavir-induced serious, idiosyncratic, adverse drug reactions (ADRs) and human leukocyte antigen-B*5701 (HLA-B*5701). Studies also found that abacavir-induced ADRs were seldom observed in patients carrying the HLA-B*5801 subtype. HLA-B*5801 of the same serotype (B17) as B*5701 differs by only 4 amino acids from B*5701. It is believed that because of these sequence differences, HLA-B*5801 cannot bind the specific peptides which are required for HLA-B*5701 to stimulate the T cell immune response. Thus, the difference in peptide binding profiles between HLA-B*5701 and B*5801 is an important clue for exploring the mechanisms of abacavir-induced ADRs. VHSE (principal component score vector of hydrophobic, steric, and electronic properties), a set of amino acid structural descriptors, was employed to establish QSAR models of peptide-binding affinities of HLA-B*5701 and B*5801. Optimal linear SVM (support vector machine) models with high predictive capabilities were obtained for both B*5701 and B*5801. The R 2 (coefficient of determination), Q 2 (cross-validated R 2), and R PRE 2 (R 2 of test set) of two optimal models were 0.7530, 0.7037, 0.6153 (B*5701) and 0.6074, 0.5966, 0.5762 (B*5801), respectively. For B*5701 and B*5801, the mutations in positions 45 (MET-THR) and 46 (ALA-GLU) have little influence on the selection specificity of the P2 position of the bound peptide. However, the mutation in position 97 (VAL-ARG) greatly influences the selection specificity of the P7 position. HLA-B*5701 prefers the bulky and positively charged amino acids at the P7 position. In contrast, HLA-B*5801 prefers the non-polar hydrophobic amino acids at the P7 position while positively charged amino acids are unfavored.
Human Leukocyte Antigen (HLA) Class I Restricted Epitope Discovery in Yellow Fewer and Dengue Viruses: Importance of HLA Binding Strength  [PDF]
Ole Lund, Eduardo J. M. Nascimento, Milton Maciel, Morten Nielsen, Mette Voldby Larsen, Claus Lundegaard, Mikkel Harndahl, Kasper Lamberth, S?ren Buus, Jér?me Salmon, Thomas J. August, Ernesto T. A. Marques
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026494
Abstract: Epitopes from all available full-length sequences of yellow fever virus (YFV) and dengue fever virus (DENV) restricted by Human Leukocyte Antigen class I (HLA-I) alleles covering 12 HLA-I supertypes were predicted using the NetCTL algorithm. A subset of 179 predicted YFV and 158 predicted DENV epitopes were selected using the EpiSelect algorithm to allow for optimal coverage of viral strains. The selected predicted epitopes were synthesized and approximately 75% were found to bind the predicted restricting HLA molecule with an affinity, KD, stronger than 500 nM. The immunogenicity of 25 HLA-A*02:01, 28 HLA-A*24:02 and 28 HLA-B*07:02 binding peptides was tested in three HLA-transgenic mice models and led to the identification of 17 HLA-A*02:01, 4 HLA-A*2402 and 4 HLA-B*07:02 immunogenic peptides. The immunogenic peptides bound HLA significantly stronger than the non-immunogenic peptides. All except one of the immunogenic peptides had KD below 100 nM and the peptides with KD below 5 nM were more likely to be immunogenic. In addition, all the immunogenic peptides that were identified as having a high functional avidity had KD below 20 nM. A*02:01 transgenic mice were also inoculated twice with the 17DD YFV vaccine strain. Three of the YFV A*02:01 restricted peptides activated T-cells from the infected mice in vitro. All three peptides that elicited responses had an HLA binding affinity of 2 nM or less. The results indicate the importance of the strength of HLA binding in shaping the immune response.
HLA-Associated Immune Pressure on Gag Protein in CRF01_AE-Infected Individuals and Its Association with Plasma Viral Load  [PDF]
Goragoch Gesprasert,Nuanjun Wichukchinda,Masahiko Mori,Teiichiro Shiino,Wattana Auwanit,Busarawan Sriwanthana,Panita Pathipvanich,Pathom Sawanpanyalert,Toshiyuki Miura,Prasert Auewarakul,Arunee Thitithanyanont,Koya Ariyoshi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011179
Abstract: The human leukocyte antigen (HLA)-restricted cytotoxic T-lymphocyte (CTL) immune response is one of the major factors determining the genetic diversity of human immunodeficiency virus (HIV). There are few population-based analyses of the amino acid variations associated with the host HLA type and their clinical relevance for the Asian population. Here, we identified HLA-associated polymorphisms in the HIV-1 CRF01_AE Gag protein in infected married couples, and examined the consequences of these HLA-selected mutations after transmission to HLA-unmatched recipients.
HLA-B*5701 frequency in Chilean HIV-infected patients and in general population
Poggi, Helena;Vera, Alejandra;Lagos, Marcela;Solari, Sandra;Rodríguez P, Luis;Pérez, Carlos M;
Brazilian Journal of Infectious Diseases , 2010, DOI: 10.1590/S1413-86702010000500015
Abstract: it has been demonstrated that hla-b*5701 screening reduces the risk for hypersensitivity reaction to abacavir in hiv-infected patients. since b*5701 prevalence varies among different populations, it is important to determine the carrier frequency prior to its use for the screening of hiv-infected patients.the aim of this study was to determine hla-b*5701 carrier frequency in chilean general population and hiv-infected patients referred for b*5701 typing. for that purpose 300 blood bank donors and 492 abacavir-na?ve hiv-infected patients from chile were screened for b*5701 by a sequence specific primer pcr.we detected 14/300 (4.7%) b*57-positive individuals in the chilean general population, 11 (3.7%) were b*5701 positive, and 3 (1%) had another subtype.all were heterozygous,thus a b*5701 allele frequency of 2% was determined.eleven of 492 (2.2 %) hiv-patients carried a b*5701 allele. the difference between these frequencies is probably due to slow progression of hiv infection in hla-b*5701 carriers, thus less patients would require antiretroviral therapy and b*5701 typing. considering the usefulness of b*5701 screening, its prevalence in the chilean general population,and the availability of a validated method,we conclude that hla-b*5701 typing in chilean hiv-infected patients about to initiate abacavir treatment is strongly recommended
Human Leukocyte Antigen-G (HLA-G) Polymorphism and Expression in Breast Cancer Patients  [PDF]
Seri Jeong, Seho Park, Byeong-Woo Park, Younhee Park, Oh-Joong Kwon, Hyon-Suk Kim
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098284
Abstract: Human leukocyte antigen-G (HLA-G) is known to be implicated in a tumor-driven immune escape mechanism in malignancies. The purpose of this study was to investigate HLA-G polymorphism and expression in breast cancer. HLA-G alleles were determined by direct DNA sequencing procedures from blood samples of 80 breast cancer patients and 80 healthy controls. Soluble HLA-G (sHLA-G) was measured by enzyme-linked immunosorbent assay (ELISA) from serum specimens. HLA-G expression in breast cancer lesions was also analyzed by immunohistochemistry staining. The presence of HLA-G 3′ untranslated region (UTR) 14-bp sequence was analyzed and found to be associated with reduced risk of breast cancer susceptibility based on HLA-G expression in tissues (P = 0.0407). Levels of sHLA-G were higher in the breast cancer group (median 117.2 U/mL) compared to the control group (median 10.1 U/mL, P<0.001). The area under the receiver operating characteristic curve (AU-ROC) values of sHLA-G for differentiating breast cancer from normal controls and for detecting metastasis from other stages of breast cancer were 0.89 and 0.79, respectively. HLA-G polymorphism and expression may be involved in breast carcinogenesis and sHLA-G concentrations could be used as a diagnostic marker for detecting breast cancer.
Importance of Human Leukocyte Antigen (HLA) Class I and II Alleles on the Risk of Multiple Sclerosis  [PDF]
Jenny Link, Ingrid Kockum, ?slaug R. Lorentzen, Benedicte A. Lie, Elisabeth G. Celius, Helga Westerlind, Marie Schaffer, Lars Alfredsson, Tomas Olsson, Boel Brynedal, Hanne F. Harbo, Jan Hillert
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036779
Abstract: Multiple sclerosis (MS) is a complex disease of the central nervous system of unknown etiology. The human leukocyte antigen (HLA) locus on chromosome 6 confers a considerable part of the susceptibility to MS, and the most important factor is the class II allele HLA-DRB1*15:01. In addition, we and others have previously established a protective effect of HLA-A*02. Here, we genotyped 1,784 patients and 1,660 healthy controls from Scandinavia for the HLA-A, HLA-B, HLA-C and HLA-DRB1 genes and investigated their effects on MS risk by logistic regression. Several allele groups were found to exert effects independently of DRB1*15 and A*02, in particular DRB1*01 (OR = 0.82, p = 0.034) and B*12 (including B*44/45, OR = 0.76, p = 0.0028), confirming previous reports. Furthermore, we observed interaction between allele groups: DRB1*15 and DRB1*01 (multiplicative: OR = 0.54, p = 0.0041; additive: AP = 0.47, p = 4×10?06), DRB1*15 and C*12 (multiplicative: OR = 0.37, p = 0.00035; additive: AP = 0.58, p = 2.6×10?05), indicating that the effect size of these allele groups varies when taking DRB1*15 into account. Analysis of inferred haplotypes showed that almost all DRB1*15 bearing haplotypes were risk haplotypes, and that all A*02 bearing haplotypes were protective as long as they did not carry DRB1*15. In contrast, we found one class I haplotype, carrying A*02-C*05-B*12, which abolished the risk of DRB1*15. In conclusion, these results confirms a complex role of HLA class I and II genes that goes beyond DRB1*15 and A*02, in particular by including all three classical HLA class I genes as well as functional interactions between DRB1*15 and several alleles of DRB1 and class I genes.
Effect of the human leukocyte antigen HLA-DRB1 and anti-cyclic citrullinated peptide on the outcome of rheumatoid arthritis patients
Farouk, H.M.;Mansour, H.E.;Rahman, S.A.;Mostafa, A.A.;Shamy, H.A.;Zarouk, W.A.;
Brazilian Journal of Medical and Biological Research , 2009, DOI: 10.1590/S0100-879X2009000900010
Abstract: our objective was to determine whether the presence of the human leukocyte antigen hla-drb1 locus is associated with production of anti-cyclic citrullinated peptide antibodies (anti-ccp abs) and to what extent they are associated with increased susceptibility to and severity of rheumatoid arthritis (ra) in egyptian patients. twenty-nine ra patients gave informed consent to participate in a case-control study that was approved by the ain shams university medical ethics committee. ra disease activity and severity were determined using the simplified disease activity index and larsen scores, respectively. we used a wide scale national study on the pattern of hla typing in normal egyptians as a control study. anti-ccp abs and hla-drb1 typing were determined for all subjects. the alleles most strongly associated with ra were hla-drb1 [*01 , *04 and *06] (41.4%). ra patients with serum anti-ccp ab titers above 60 u/ml had a significantly higher frequency of hla-drb1*01 (58.3%) and hla-drb1*04 alleles (83.3%). significant positive correlations were found between serum and synovial anti-ccp ab titer, ra disease activity, and severity (r = 0.87, 0.66 and 0.63, respectively; p < 0.05). hla-drb1 se+ alleles [*01 and *04] were highly expressed among egyptian ra patients. the presence of these alleles was associated with higher anti-ccp ab titer, active and severe ra disease. early determination of hla-drb1 se+ alleles and serum anti-ccp ab could facilitate the prediction of the clinical course and prognosis of ra when first evaluated leading to better disease control.
Evaluation of Human Leukocyte Antigen-A (HLA-A), Other Non-HLA Markers on Chromosome 6p21 and Risk of Nasopharyngeal Carcinoma  [PDF]
Wan-Lun Hsu, Ka-Po Tse, Sharon Liang, Yin-Chu Chien, Wen-Hui Su, Kelly J. Yu, Yu-Juen Cheng, Ngan-Ming Tsang, Mow-Ming Hsu, Kai-Ping Chang, I-How Chen, Tzu-I Chen, Czau-Siung Yang, Alisa M. Goldstein, Chien-Jen Chen, Yu-Sun Chang, Allan Hildesheim
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042767
Abstract: Background The association between human leukocyte antigen (HLA) genes (located in the Major Histocompatibility Complex [MHC] region of chromosome 6p21) and NPC has been known for some time. Recently, two genome-wide association studies (GWAS) conducted in Taiwan and China confirmed that the strongest evidence for NPC association was mapped to the MHC region. It is still unclear, however, whether these findings reflect direct associations with Human Leukocyte Antigen (HLA) genes and/or to other genes in this gene-rich region. Methods To better understand genetic associations for NPC within the MHC region of chromosome 6, we conducted an evaluation that pooled two previously conducted NPC case-control studies in Taiwan (N = 591 cases and N = 521 controls). PCR-based genotyping was performed for 12 significant SNPs identified within 6p21 in the Taiwan NPC GWAS and for the HLA-A gene (exons 2 and 3). Findings After confirming homogeneity between the two studies, pooled odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. We found that HLA-A (p-trend = 0.0006) and rs29232 (within the GABBR1 gene; p-trend = 0.005) were independent risk factors for NPC after adjustment for age, gender, study and each other. NPC risk was highest among individuals who were homozygous for the HLA-A*0207 risk allele and carriers of the rs29232 risk allele (A). Conclusion Our study suggests that most of the SNPs significantly associated with NPC from GWAS reflect previously identified HLA-A associations. An independent effect of rs29232 (GABBR1), however, remained, suggesting that additional genes within this region might be associated with NPC risk.
Human leukocyte antigen associations and c-reactive protein levels in lebanese patients with aggressive periodontitis—HLA and CRP in aggressive periodontitis  [PDF]
Marita Chakhtoura, Nada M. Souccar, Nayla S. Al-Akl, Alexander M. Abdelnoor
Open Journal of Stomatology (OJST) , 2011, DOI: 10.4236/ojst.2011.12005
Abstract: Background: Periodontal disease, which affects tooth- supporting structures, results from disequilibrium between the oral micro flora and host defense mecha- nisms. It has been classified into chronic (CP) or ag- gressive (AP) periodontitis according to disease onset, localization and progression. Because of their invol- vement in generating immune responses, Human Leukocyte Antigen (HLA) alleles are considered can- didate genetic risk markers for periodontitis. Addi- tionally, periodontitis appears to contribute to the severity of some systemic conditions such as cardio- vascular disease and adverse pregnancy outcome as indicated by elevated levels of C-reactive protein (CRP). Aim: The aims of this study were to deter- mine if there is an HLA-AP association in Lebanese patients, and to determine CRP levels in patients and compare them to those in healthy controls. Materials and methods: The study groups included 26 patients with AP and 39 healthy controls. HLA profiles were determined by DNA typing and CRP levels by ELISA. Results: HLA-A*30 (P-value = 0.010), HLA- B*41 (P1 = 0.012 and P2 = 0.014), HLA-DRB1*13 (P1 = 0.031 and P2 = 0.063) alleles seemed to be associ- ated with protection against AP in Lebanese patients. No linkage disequilibrium existed between alleles as-sociated with AP. Ten of 26 AP patients (38.5%) and 10 of 39 (25.7%) controls had elevated CRP lev- els. Conclusion: In conclusion, protective, but no sus- ceptible HLA alleles were detected in AP. CRP levels were not elevated in the entire AP group, and were not significantly different from controls. No linkage disequilibrium existed between alleles.
Human Leukocyte Antigens and HIV Type 1 Viral Load in Early and Chronic Infection: Predominance of Evolving Relationships  [PDF]
Jianming Tang,Rakhi Malhotra,Wei Song,Ilene Brill,Liangyuan Hu,Paul K. Farmer,Joseph Mulenga,Susan Allen,Eric Hunter,Richard A. Kaslow
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009629
Abstract: During untreated, chronic HIV-1 infection, plasma viral load (VL) is a relatively stable quantitative trait that has clinical and epidemiological implications. Immunogenetic research has established various human genetic factors, especially human leukocyte antigen (HLA) variants, as independent determinants of VL set-point.
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