HBsAg和抗HBs抗体共存患者血清中HBV准种全长基因组的进化。

StephenW

Sci Rep. 2017 Apr 6;7(1):661. doi: 10.1038/s41598-017-00694-8.
Evolution of full-length genomes of HBV quasispecies in sera of patients with a coexistence of HBsAg and anti-HBs antibodies.
Zhou TC1, Li X1, Li L1, Li XF2, Zhang L3, Wei J4.
Author information

1    Central lab, Liver disease research center, the second people's hospital of Yunnan Province, Kunming, Yunnan Province, China.
2    Clinical laboratory, the third people's hospital of Kunming City, Kunming, Yunnan Province, China.
3    Central lab, Liver disease research center, the second people's hospital of Yunnan Province, Kunming, Yunnan Province, China. [email protected].
4    Central lab, Liver disease research center, the second people's hospital of Yunnan Province, Kunming, Yunnan Province, China. [email protected].

Abstract

Although the evolutionary changes of viral quasispecies are correlated to the pathological status of a disease, little is known in the coexistence of hepatitis B surface antigen (HBsAg) and antibodies to these antigens (anti-HBs). To examine evolutionary changes in hepatitis B virus (HBV) and their relationship to the coexistence of HBsAg and anti-HBs antibodies, HBV genomes in patients with a coexistence of HBsAg and anti-HBs antibodies (experimental group) and HBsAg positive without anti-HBs (control group) were assessed. Our results showed that quasispecies diversity was significantly higher in the experimental group for large HBsAg (LHBsAg), middle HBsAg (MHBsAg), and HBsAg genes. LHBsAg harbored dN/dS values eight times higher in the experimental group; however, the mean dN/dS ratios in genes HbxAg, Pol and PreC/C of the experimental patients had an opposite trend. Phylogenetic trees in the experimental group were more complex than the control group. More positive selection sites, mutations and deletions were observed in the experimental group in specific regions. Furthermore, several amino acid variants in epitopes were potentially associated with the immune evasion. In conclusion, cumulative evolutionary changes in HBV genome that facilitate immune evasion provide insights into the genetic mechanism of a coexistence of HBsAg and anti-HBs antibodies.

PMID:
    28386078
DOI:
    10.1038/s41598-017-00694-8

StephenW

Sci Rep。2017 Apr 6; 7（1）：661。 doi：10.1038 / s41598-017-00694-8。
HBsAg和抗HBs抗体共存患者血清中HBV准种全长基因组的进化。
Zhou TC1，Li X1，Li L1，Li XF2，Zhang L3，Wei J4。
作者信息

1中央实验室，肝病研究中心，云南省第二人民医院，云南昆明，中国。
2临床实验室，昆明市昆明市第三人民医院，云南省昆明市。
3中央实验室，肝病研究中心，云南省第二人民医院，云南昆明，中国。 [email protected]。
4中央实验室，肝病研究中心，云南省第二人民医院，云南昆明，云南省。 [email protected]。

抽象

虽然病毒准种的进化变化与疾病的病理状态相关，但在乙型肝炎表面抗原（HBsAg）和这些抗原（抗HBs）的抗体共存下，很少有人知道。为了检查乙型肝炎病毒（HBV）的进化变化及其与HBsAg和抗HBs抗体共存的关系，HBsAg和抗HBs抗体（实验组）共存的患者和无HBsAg阳性的HBsAg阳性患者的HBV基因组（对照组）。我们的研究结果表明，实验组大HBsAg（LHBsAg），中HBsAg（MHBsAg）和HBsAg基因的准种多样性显着较高。 LHBsAg的dN / dS值在实验组中高出8倍;然而，实验患者的基因HbxAg，Pol和PreC / C中的平均dN / dS比率具有相反的趋势。实验组中的系统发育树比对照组更复杂。在特定区域的实验组中观察到更多的阳性选择位点，突变和缺失。此外，表位中的几种氨基酸变体可能与免疫逃避有关。总之，促进免疫逃避的HBV基因组的累积进化变化提供了HBsAg和抗HBs抗体共存的遗传机制的见解。

PMID：
    28386078
DOI：
    10.1038 / s41598-017-00694-8

StephenW

It is well-known in the medical field that antibodies to hepatitis B surface antigen (HBsAg), anti-HBs, are capable of neutralizing HBsAg and clearance of HBV, which is characterized by the emergence of anti-HBs and the disappearance of HBsAg from peripheral blood4. Hence it is a conundrum when both HBsAg and anti-HBs are present in same serological profile5. However, incidences of coexisting of HBsAg and anti-HBs among HBsAg positive patients has been increasingly reported, which is nearly 5% in China5, 21% in Japan6, 36% in Netherlands7, 2.8% in France8, 2.9% in South Korea9, varies from 2.8% to 36%5,6,7,8,9,10 and progressively increases with patient age from 40 to 70 years old11.

The molecular mechanism underlying the emergence of coexisting HBsAg and anti-HBs remains unclear. Several studies have been attributed to the selection of immune escape mutations in HBV genome, especially the determinant region (amino acids 124–147) of HBsAg, from one or a few viral strains4, 8, 12,13,14. Viral replication and the host immune response are two vital processes that interplay during HBV infection. The compact HBV genome contains four overlapping regions: preS/S completely overlaps with polymerase region, and HBxAg and HBcAg each partly overlap with polymerase region15, 16. These regions encode 7 proteins: DNA polymerase (Pol), three envelope proteins (LHBsAg, MHBsAg and HBsAg), core protein (HBcAg), X protein (HBx), and e protein (HBeAg). LHBsAg, MHBsAg, and HBsAg are structural proteins, while HBx regulates viral DNA replication and interferes with the host cell17. There are three types of Pol acting on DNA replication, and HBeAg may contribute to T cell immunological tolerance18.

Owing to a high replication rate and a lack of proof-reading capacity during reverse transcription, HBV exist as quasispecies19. Quasispecies is a population of closely related, but genetically distinct variants capable surviving living in a mutagenic environment19. The spectrum of mutants possess differing levels of fitness in a range of environments20. Thus, the serological profiles of HBV patients may be affected by competition among viral variants within quasispecies (differences in replicative efficiency)19 and/or host immune reactivity21.

StephenW

在医学领域众所周知，乙型肝炎表面抗原（HBsAg），抗HBs的抗体能够中和HBsAg和清除HBV，其特征在于抗HBs的出现和HBsAg的消失外周血4。因此，当HBsAg和抗HBs都存在于相同的血清学特征5时，这是一个难题。然而，HBsAg阳性患者HBsAg和抗HBs共存事件越来越多，中国5％，日本6％，荷兰7％，法国3.8％，法国2.8％，韩国2.9％从2.8％增加到36％5,6,7,8,9,10，患者年龄从40岁到70岁逐渐增加11。

共存HBsAg和抗HBs的基因分子机制尚不清楚。一些研究被归因于HBV基因组中免疫逃逸突变的选择，特别是HBsAg的决定簇（氨基酸124-147），来自一个或几个病毒株4,8,12,13,14。病毒复制和宿主免疫应答是HBV感染过程中相互作用的两个重要过程。紧密的HBV基因组包含四个重叠区域：preS / S与聚合酶区域完全重叠，HBxAg和HBcAg每个部分与聚合酶区域15,16重叠。这些区域编码7个蛋白质：DNA聚合酶（Pol），三个包膜蛋白（LHBsAg，MHBsAg和HBsAg），核心蛋白（HBcAg），X蛋白（HBx）和e蛋白（HBeAg）。 LHBsAg，MHBsAg和HBsAg是结构蛋白，而HBx调节病毒DNA复制并干扰宿主细胞17。有三种类型的Pol作用于DNA复制，HBeAg可能有助于T细胞免疫耐受18。

由于复制率高，逆转录中缺乏校对阅读能力，HBV作为准种存在19。准种是一个密切相关的群体，但遗传上独特的变异体能够在致突变环境中生存19。突变体的光谱在一系列环境中具有不同的适应度20。因此，HBV患者的血清学特征可能受到准种间病毒变体（复制效率差异）19和/或宿主免疫反应性21的竞争的影响。

StephenW

http://www.nature.com/articles/s41598-017-00694-8

HBV-lost

SR的文章，大打折扣啊