Hepatitis B virus movement through the hepatocyte: An update

Abstract

Viruses are obligate intracellular pathogens that utilize cellular machinery for many aspects of their propagation and effective egress of virus particles from host cells is one important determinant of virus infectivity. Hijacking host cell processes applies in particular to the hepatitis B virus (HBV), as its DNA genome with about 3 kb in size is one of the smallest viral genomes known. HBV is a leading cause of liver disease and still displays one of the most successful pathogens in human populations worldwide. The extremely successful spread of this virus is explained by its efficient transmission strategies and its versatile particle types, including virions, empty envelopes, naked capsids, and others. HBV exploits distinct host trafficking machineries to assemble and release its particle types including nucleocytoplasmic shuttling transport, secretory, and exocytic pathways, the Endosomal Sorting Complexes Required for Transport pathway, and the autophagy pathway. Understanding how HBV uses and subverts host membrane trafficking systems offers the chance of obtaining new mechanistic insights into the regulation and function of this essential cellular processes. It can also help to identify potential targets for antiviral interventions. Here, I will provide an overview of HBV maturation, assembly, and budding, with a focus on recent advances, and will point out areas where questions remain that can benefit from future studies. Unless otherwise indicated, almost all presented knowledge was gained from cell culture-based, HBV in vitro-replication and in vitro-infection systems.

Impact of core protein naturally selected mutants associated with HBeAg‐negative status in HBV biosynthesis

“…Finally, HBVwt/C4 mutant presented high levels of extracellular pgRNA, but no difference in extracellular capsid‐associated DNA, suggesting that HBVwt/C4 variants secret more premature pgRNA‐containing particles in which reverse transcription has not been completed. Notably, HBVwt/C4 variant carries mutations in the late assembly domain‐like PPAY motif (P130A and A131P) involved in the transport of mature nucleocapsids to multivesicular bodies via the ESCRT system for viral release 26,27 . It is likely that the mutations in this domain increase extracellular pgRNA levels through the secretion of immature particles via an ESCRT‐independent pathway in detriment of viral progeny production.…”

Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies

“…Previous research shows that HBV-related antigens, namely HBcAg and HBsAg, can increase CD4+ T cell production of inhibitory molecules. Chuang et al [ 67 ] found that HBcAg enhanced PD-1 expression on CD4+ T cells, disrupting their function via JNK, ERK, and PI3K/AKT signaling pathways[ 79 ]. Moreover, the expression of human protein inhibitors of activated STAT1 (dependent on ERK and p38 MAPK signaling pathways) increased in CHB patients, making standard therapies ineffectual.…”

Interconnection of cellular autophagy and endosomal vesicle trafficking and its role in hepatitis B virus replication and release

“…The study conducted by Volker Bruss's group demonstrated that the pre-S sequence between Arg 103 and Ser 124 promotes HBV virion assembly ( Bruss, 1997 ). HBcAg forms the icosahedral virus capsid and consists of 183 residues, which can be divided into an assembly domain and a domain responsible for viral genome packaging and replication (arginine-rich RNA-binding C Terminal Domain, CTD) ( Liu et al., 2018 ; Prange, 2022 ; Venkatakrishnan and Zlotnick, 2016 ; Walker et al., 2011 ). Apart from the virologic factors, HBV assembly is also greatly influenced by cellular vesicle trafficking pathways, such as endosomal vesicle trafficking and autophagy, which will be elaborated in the subsequent discussion.…”