Virion Secretion of Hepatitis B Virus Naturally Occurring Core Antigen Variants

Abstract

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.

Amino Acid Polymorphism in Hepatitis B Virus Associated With Functional Cure

“…13 To date, this amino acid substitution, I97L, has been investigated in vitro. 16,[28][29][30][31][32] Yuan et al 16 analyzed the cell culture-generated HBV-I97L virus by density gradient and demonstrated that this virus mainly contains a SS HBV DNA genome, even in the enveloped virion in the HBsAg-rich fraction, although the HBV-wt virus in the same fraction predominantly contains a RC HBV DNA genome. Recently, Wu et al 31 investigated this amino acid substitution in vivo by using the mouse-hydrodynamic injection system of HBV molecular clones and suggested that HBV-I97L releases HBV virions with single-stranded genomes.…”

The Role of Exosome and the ESCRT Pathway on Enveloped Virus Infection

“…Hepatitis B virus (HBV) is an encapsulated, DNA-containing Pararetrovirus, which is one of the most successful pathogens in the world, and there is no radical cure for HBV infection at present [116]. As reported, late endosomes and MVB are used by HBV for assembly and release [117], and the budding and release of HBV virions are related to ESCRT-related molecules [116,[118][119][120]. For example, CD63 was found to co-locate with HBV protein in infected liver cells [117].…”

Significance of hepatitis B virus capsid dephosphorylation via polymerase

“…Another highly popular concept is that core de-P could facilitate, or is required, for HBV virion secretion [ 44 , 52 ]. Using a biochemistry approach in a duck hepatitis B virus (DHBV) model, Pugh et al [ 44 ] compared HBc phosphorylation between the intracellular capsids and secreted extracellular virions.…”