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首页> 外文期刊>Emerging microbes & infections. >Key mutations in the C-terminus of the HBV surface glycoprotein correlate with lower HBsAg levels in vivo , hinder HBsAg secretion in vitro and reduce HBsAg structural stability in the setting of HBeAg-negative chronic HBV genotype-D infection
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Key mutations in the C-terminus of the HBV surface glycoprotein correlate with lower HBsAg levels in vivo , hinder HBsAg secretion in vitro and reduce HBsAg structural stability in the setting of HBeAg-negative chronic HBV genotype-D infection

机译：HBV表面糖蛋白的C-末端中的关键突变与体内较低的HBsAg水平相关，在体外阻碍HBsAg分泌，降低HbsAg阴性慢性HBV基因型-D感染的结构稳定性

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div class="hlFld-Abstract test" Increasing evidences suggest that HBsAg-production varies across HBV-genotypes. HBsAg C-terminus plays a crucial role for HBsAg-secretion. Here, we evaluate HBsAg-levels in different HBV-genotypes in HBeAg-negative chronic infection, the correlation of specific mutations in HBsAg C-terminus with HBsAg-levels in-vivo, their impact on HBsAg-secretion in-vitro and on structural stability in-silico . HBsAg-levels were investigated in 323 drug-na?ve HBeAg-negative patients chronically infected with HBV genotype-D( N =?228), -A( N =?65) and -E( N =?30). Genotype-D was characterized by HBsAg-levels lower than genotype-A and -E (3.3[2.7–3.8]IU/ml; 3.8[3.5–4.2]IU/ml and 3.9[3.7–4.2]IU/ml, P ?0.001). Results confirmed by multivariable analysis correcting for patients’demographics, HBV-DNA, ALT and infection-status. In genotype-D, specific C-terminus mutations (V190A-S204N-Y206C-Y206F-S210N) significantly correlate with HBsAg1000IU/ml( P -value from 0.001 to 0.04). These mutations lie in divergent pathways involving other HBsAg C-terminus mutations: V190A?+?F220L (Phi?=?0.41, P =?0.003), S204N?+?L205P (Phi?=?0.36, P =?0.005), Y206F?+?S210R (Phi?=?0.47, P ?0.001) and S210N?+?F220L (Phi?=?0.40, P =?0.006). Notably, patients with these mutational pairs present HBsAg-levels 1log lower than patients without them( P -value from 0.003 to 0.02). In-vitro , the above-mentioned mutational pairs determined a significant decrease in HBsAg secretion-efficiency compared to wt( P -value from 0.001 to 0.02). Structurally, these mutational pairs reduced HBsAg C-terminus stability and determined a rearrangement of this domain. In conclusion, HBsAg-levels in genotype-D are significantly lower than in genotype-A and -E in HBeAg-negative patients. In genotype-D, specific mutational clusters in HBsAg C-terminus correlate with lower HBsAg-levels in-vivo , hamper HBsAg-release in-vitro and affect its structural stability, supporting their detrimental role on HBsAg-secretion. In this light, genotypic-testing can be a valuable tool to optimize the clinical interpretation of HBsAg in genotype-D and to provide information on HBV-pathogenicity and disease-progression.
机译：Div类=“HLFLD-摘要测试”>越来越多的证据表明HBsAg-生产在HBV-基因型中变化。 HBsAg C-Terminus对HBsAg分泌起着至关重要的作用。在这里，我们评估HBSG-阴性慢性感染中不同HBV-基因型的HBsAg-infum，HBsAg C-末端的特定突变与体内HBsAg水平的相关性，它们对体外和结构稳定性对HbsAg分泌的影响在硅中。在323次药物-NA'VE HBEAG-阴性患者中研究了HBsAg-physe患者，慢性感染HBV基因型-D（n =Δ228），-a（n =Δ65）和-e（n =Δ30）。基因型-d的特征在于低于基因型-a和-e（3.3 [2.7-3.8] Iu / ml; 3.8 [3.5-4.2] Iu / ml和3.9 [3.7-4.2] Iu / ml，p < ？0.001）。结果通过多变量分析校正患者的审查，HBV-DNA，ALT和感染状态证实。在基因型-D中，特异性的C-末端突变（V190A-S204N-Y206C-Y206F-S210N）与HBsAg <1000iu / ml显着相关（P-value <0.001〜0.04）。这些突变位于涉及其他HBsAg C-末端突变的发散途径：V190A？+ΔF220L（PHI？= 0.41，P = 0.41，P = 0.003），S204N？+？L205P（PHI？= 0.36，P = 0.005）， Y206F？+？S210R（PHI？= 0.47，P <0.001）和S210N？+ΔF220L（PHI？=？0.40，P = 0.006）。值得注意的是，患有这些突变对的患者呈现比没有它们的患者低的HBsAg-Levog（P-value从0.003〜0.02）。在体外，与WT相比，上述突变对确定HbsAg分泌效率的显着降低（P-0.001至0.22）。在结构上，这些突变对降低了HBsAg C-末端稳定性并确定了该结构域的重排。总之，基因型-D中的HBsAg-inds显着低于HBeAg阴性患者的基因型-A和-E。在基因型-D中，HBsAg C-末端的特异性突变簇与体内的较低HBsAg水平相关，阻碍HBsAg-释放体外，影响其结构稳定性，支持其对HBsAg分泌的不利作用。在这种光中，基因型测试可以是有价值的工具，以优化HBsAg在基因型-D中的临床解释，并提供关于HBV-致病性和疾病的信息。

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