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.
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.作者: StephenW 时间: 2017-4-10 14:24