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.
Highlights
Hepatitis B virus (HBV) is a major human pathogen [1,2]
Immature secretion is an evolutionarily conserved pheThis is a widely observed phenotype since it is true in HBV subtypes ayw [17], adr [18] and nomenon found in other non-human hepadnaviruses, such as snow goose hepatitis B virus genotype A [19]
Defect in the mutant HBV genome per se. Nor is it clear if the extracellular phenotype replication, in the plus-strand DNA synthesis. It is unclear if this deficiency of immature virion secretion could originate from any aberrant or super-efficient corein viral DNA synthesis is due to a trans-defect in the mutant F97L core protein, or a cisenvelope interaction in virion morphogenesis, which in turn diminishes the intracellular defect in the mutant HBV genome per se
Summary
HBV could lead to chronic hepatitis, cirrhosis and hepatoma [3,4]. At present, no curative treatment can effectively eradicate the virus from patients [5,6,7]. For wild type HBV in cell culture, the virions containing a mature genome (Figure 2A) are preferentially secreted into the meratio between the secreted mature genome and immature genome is generally around 4 dium [16]. This dogma is violated by mutant 97L. Immature secretion is an evolutionarily conserved pheThis is a widely observed phenotype since it is true in HBV subtypes ayw [17], adr [18] and nomenon found in other non-human hepadnaviruses, such as snow goose hepatitis B virus genotype A [19]. Using strand-specific probes in Southern blot analysis, Yuan et al [17] demonstrated that one intracellular phenotype
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