Hepatitis B virus middle surface antigen loss promotes clinical variant persistence in mouse models

Junyu Lin; Jing Li; Peilin Xie; Yue Han; Demin Yu; Jia Chen; Xinxin Zhang

doi:10.1080/21505594.2021.1999130

Hepatitis B virus middle surface antigen loss promotes clinical variant persistence in mouse models

Virulence. 2021 Dec;12(1):2868-2882. doi: 10.1080/21505594.2021.1999130.

Authors

Junyu Lin¹, Jing Li¹, Peilin Xie¹, Yue Han¹, Demin Yu¹, Jia Chen¹, Xinxin Zhang¹

Affiliation

¹ Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Hepatitis B virus (HBV) middle surface antigen (MHBs) mutation or deletion occurs in patients with chronic HBV infection. However, the functional role of MHBs in HBV infection is still an enigma. Here, we reported that 7.33% (11/150) isolates of CHB patients had MHBs start codon mutations compared with 0.00% (0/146) in acute hepatitis B (AHB) patients. Interestingly, MHBs loss accounted for 11.88% (126/1061) isolates from NCBI GenBank, compared with 0.09% (1/1061) and 0.00% (0/1061) for HBV large surface antigen (LHBs) loss and HBV small surface antigen (SHBs) loss, respectively. One persistent HBV clone of genotype B (B56, MHBs loss) from a CHB patient was hydrodynamically injected into BALB/c mice. B56 persisted for >70 weeks in BALB/c mice, whereas B56 with restored MHBs (B56^M+) was quickly cleared within 28 days. Serum cytokine assays demonstrated that CXCL1, CXCL2, IL-6 and IL-33 were significantly increased during rapid HBV clearance in B56^M+ mice. Furthermore, the enhancers and promoters of B56 were proved to be required for B56 persistence in mice. Ablating MHBs expression improved the persistence of a new clone (HBV1.3, genotype B) which was recreated by using enhancers and promoters of B56. These data demonstrated that MHBs deletion can promote the persistence of specific HBV variants in a hydrodynamic mouse model. MHBs re-expression restored a rapid clearance of HBV, which was accompanied by cytokine responses including the elevation of CXCL1, CXCL2, IL-6 and IL-33.

Keywords: chronic infection; cytokines; hepatitis B virus; middle surface antigen; start codon mutation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Surface
Disease Models, Animal
Hepatitis B Surface Antigens / genetics
Hepatitis B virus* / genetics
Humans
Interleukin-33*
Interleukin-6 / genetics
Mice
Mice, Inbred BALB C

Substances

Antigens, Surface
Hepatitis B Surface Antigens
Interleukin-33
Interleukin-6

Grants and funding

This work was supported by the National Major Science and Technology Projects of China [2018ZX10302204-001-003]; National Major Science and Technology Projects of China [2017ZX10202202]; National Natural Science Foundation of China [81672069]; National Natural Science Foundation of China [81974301]; Shanghai Municipal Science and Technology Committee [16410711900].