Virion Secretion of Hepatitis B Virus Naturally Occurring Core Antigen Variants
1
Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
2
Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
3
Chimera Bioscience Inc., No. 18 Siyuan St., Zhongzheng Dist., Taipei 10087, Taiwan
4
Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
5
TFBS Bioscience, Inc. 3F, No. 103, Ln 169, Kangning St., Xizhi Dist., New Taipei City 221, Taiwan
*
Authors to whom correspondence should be addressed.
Cells 2021, 10(1), 43; https://doi.org/10.3390/cells10010043
Received: 8 November 2020 / Revised: 21 December 2020 / Accepted: 28 December 2020 / Published: 30 December 2020
(This article belongs to the Special Issue Hepatitis B Virus and Host Interactions)
In natural infection, hepatitis B virus (HBV) core protein (HBc) accumulates frequent mutations. The most frequent HBc variant in chronic hepatitis B patients is mutant 97L, changing from an isoleucine or phenylalanine to a leucine (L) at HBc amino acid 97. One dogma in the HBV research field is that wild type HBV secretes predominantly virions containing mature double-stranded DNA genomes. Immature genomes, containing single-stranded RNA or DNA, do not get efficiently secreted until reaching genome maturity. Interestingly, HBc variant 97L does not follow this dogma in virion secretion. Instead, it exhibits an immature secretion phenotype, which preferentially secretes virions containing immature genomes. Other aberrant behaviors in virion secretion were also observed in different naturally occurring HBc variants. A hydrophobic pocket around amino acid 97 was identified by bioinformatics, genetic analysis, and cryo-EM. We postulated that this hydrophobic pocket could mediate the transduction of the genome maturation signal for envelopment from the capsid interior to its surface. Virion morphogenesis must involve interactions between HBc, envelope proteins (HBsAg) and host factors, such as components of ESCRT (endosomal sorting complex required for transport). Immature secretion can be offset by compensatory mutations, occurring at other positions in HBc or HBsAg. Recently, we demonstrated in mice that the persistence of intrahepatic HBV DNA is related to virion secretion regulated by HBV genome maturity. HBV virion secretion could be an antiviral drug target.
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Keywords:
hepatitis B virus (HBV); naturally occurring mutation; HBV core antigen; immature virion secretion; genome maturation; hydrophobic pocket; compensatory mutation; persistence; hydrodynamic mouse model
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MDPI and ACS Style
Shih, C.; Wu, S.-Y.; Chou, S.-F.; Yuan, T.-T.T. Virion Secretion of Hepatitis B Virus Naturally Occurring Core Antigen Variants. Cells 2021, 10, 43. https://doi.org/10.3390/cells10010043
AMA Style
Shih C, Wu S-Y, Chou S-F, Yuan T-TT. Virion Secretion of Hepatitis B Virus Naturally Occurring Core Antigen Variants. Cells. 2021; 10(1):43. https://doi.org/10.3390/cells10010043
Chicago/Turabian StyleShih, Chiaho; Wu, Szu-Yao; Chou, Shu-Fan; Yuan, Ta-Tung T. 2021. "Virion Secretion of Hepatitis B Virus Naturally Occurring Core Antigen Variants" Cells 10, no. 1: 43. https://doi.org/10.3390/cells10010043
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