This study was designed to establish the prevalence of HLA-B*5701 at HIV-1 infected individuals in Brazil. A total of 517 consecutive individuals were followed in this study from February 2009 through July 2011. The p...This study was designed to establish the prevalence of HLA-B*5701 at HIV-1 infected individuals in Brazil. A total of 517 consecutive individuals were followed in this study from February 2009 through July 2011. The presence of HLA-B*5701 was determined by Nested-PCR with HLA-B*57 and HLA-B*5701 sequence-specific primers (PCR-SSP). The expression of HLA-B*57 was negative in the 385 (74.5%) and positive in the 103 (19.9%) of infected individuals. Among these, the expression of HLA-B5701 was positive in the 29 (5.6%) of individuals. No demographic or ethnic differences were found between HLA-B*57/HLA-B*5701 HIV-1 negative patients, with a prevalence of Caucasians (57.1%) individuals. During the period of study, 68 patients were submited to an abacavir contain- ing regimen. The HLA-B*5701 allele was observed in 7 (10.3%) patients, with a significant incidence of Hypersensitivity reactions at 4 of them (p < 0.001). Conclusions: Although Brazilian population consists of a mixture of individuals of Caucasian, African and Native American genetic background, prevalence of HLA-B*5701 in this population is similar to the one found in pure Caucasians.展开更多
Recently, genome wide association studies showed that there is a strong association between abacavir-induced serious, idio- syncratic, adverse drag reactions （ADRs） and human leukocyte antigen-B＊5701 （HLA-B＊5701...Recently, genome wide association studies showed that there is a strong association between abacavir-induced serious, idio- syncratic, adverse drag reactions （ADRs） and human leukocyte antigen-B＊5701 （HLA-B＊5701）. Studies also found that ab- acavir-induced ADRs were seldom observed in patients carrying the HLA-B＊5801 subtype. HLA-B＊5801 of the same sero- type （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 prop- erties）, 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 ob- tained for both B＊5701 and B＇5801. The R2 （coefficient of determination）, Q2 （cross-validated R：）, and RpRE2 （R2 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 speci- ficity 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 un- favored.展开更多
文摘基于VHSE(Principal component score vector of hydrophobic,steric,and electronic properties)结构表征方法,采用支持向量机结合遗传算法变量筛选技术,分别建立B*5701和B*5801多肽亲和活性的分类预测模型,其最优线性模型内部验证的灵敏度(Sensitivity,Sen)、特异性(Specificity,Spe)、接受者操作特征曲线下面积(Area under receiver operating characteristics curve,AUC)和马休斯相关系数(Matthews coefficient of correlation,MCC)分别为77.29%、93.99%、93.02%、67.65%(B*5701)和78.08%、89.62%、88.34%、64.73%(B*5801);外部验证的Sen、Spe、AUC和MCC分别为80.02%、94.53%、94.62%、72.09%(B*5701)和77.43%、90.79%、87.98%、66.20%(B*5801)。依据最优模型,分别对B*5701和B*5801配体的亲和特性进行了细致的比较和分析,研究结果可为Abacavir的HLA-B*5701限制性药物毒副作用(Serious Adverse Drug Reactions,SADR)机理研究提供重要的参考依据。
文摘This study was designed to establish the prevalence of HLA-B*5701 at HIV-1 infected individuals in Brazil. A total of 517 consecutive individuals were followed in this study from February 2009 through July 2011. The presence of HLA-B*5701 was determined by Nested-PCR with HLA-B*57 and HLA-B*5701 sequence-specific primers (PCR-SSP). The expression of HLA-B*57 was negative in the 385 (74.5%) and positive in the 103 (19.9%) of infected individuals. Among these, the expression of HLA-B5701 was positive in the 29 (5.6%) of individuals. No demographic or ethnic differences were found between HLA-B*57/HLA-B*5701 HIV-1 negative patients, with a prevalence of Caucasians (57.1%) individuals. During the period of study, 68 patients were submited to an abacavir contain- ing regimen. The HLA-B*5701 allele was observed in 7 (10.3%) patients, with a significant incidence of Hypersensitivity reactions at 4 of them (p < 0.001). Conclusions: Although Brazilian population consists of a mixture of individuals of Caucasian, African and Native American genetic background, prevalence of HLA-B*5701 in this population is similar to the one found in pure Caucasians.
基金supported by the National Natural Science Foundation of China (Grant No. 61073135)Chongqing Natural Science Foundation(Grant No. CSTC, 2009BA5068)
文摘Recently, genome wide association studies showed that there is a strong association between abacavir-induced serious, idio- syncratic, adverse drag reactions （ADRs） and human leukocyte antigen-B＊5701 （HLA-B＊5701）. Studies also found that ab- acavir-induced ADRs were seldom observed in patients carrying the HLA-B＊5801 subtype. HLA-B＊5801 of the same sero- type （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 prop- erties）, 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 ob- tained for both B＊5701 and B＇5801. The R2 （coefficient of determination）, Q2 （cross-validated R：）, and RpRE2 （R2 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 speci- ficity 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 un- favored.
