Host Cell Rab GTPases in Hepatitis B Virus Infection

Abstract

Hepatitis B virus (HBV) is a leading cause of liver disease and is presently estimated to infect more than 250 million humans. The extremely successful spread of this virus among the human population is explained by its effective transmission strategies and its manifold particle types, including virions, empty envelopes and naked capsids. Due to its tiny genome, HBV depends on cellular machineries to thrive in infected hepatocytes. To enter, traverse and exit the cell, HBV exploits host membrane trafficking pathways, including intracellular highways directed by Rab GTPases. Here, we review recent discoveries focused on how HBV co-opts and perturbs host Rab GTPase functions with an emphasis on Rab7A- and Rab33B-mediated trafficking pathways. Rab7A plays bidirectional roles in the viral life cycle, as it promotes the endocytic uptake of HBV in early stages, but restricts exocytic virion release in late stages. In intermediate stages of HBV propagation, Rab33B is needed to guide the assembly of replicative progeny nucleocapsids. Rab33B acts together with its Atg5-12/16L1 effector, a protein complex required for autophagosome formation, suggesting the concept that HBV exploits this Rab/effector complex as an assembly scaffold and machine. We also discuss whether Rab-directed trafficking pathways engaged by HBV may be applicable to other virus families. Identification of overlapping Rab functions may offer new chances to develop broad-spectrum host-targeted antiviral strategies.

Efficient long-term amplification of hepatitis B virus isolates after infection of slow proliferating HepG2-NTCP cells

“…Supernatants of HBV-transfected HepAD38 cells harbored predominantly defective naked capsids, which were reported to exit stable HBV-transfected cells via an alternative secretion pathway compared to virions. 18 In contrast, infected HepG2-NTCPsec+ released high levels of LHBs-enveloped virions but no detectable naked capsids. An excess of secreted naked capsids is likely an aberrant product of transfected hepatoma cells where HBV replication is driven by chromosomally integrated HBV DNA, exhibiting epigenetic regulation distinct from that of viral replication driven by episomal cccDNA in infected cells.…”

Efficient and reproducible depletion of hepatitis B virus from plasma derived extracellular vesicles

“…The majority of HBsAg is incorporated into subviral particles that are formed at the ER membrane, not at the multivesicular bodies, and outnumber virions by more than a thousand‐fold (Patient et al., 2007; Tong & Revill, 2016). The secretion of subviral particles occurs via the Golgi network and the constitutive secretion pathway (Zeyen & Prange, 2018). Only a minority of HBV envelopes are transported to multivesicular bodies via uncharacterized pathways for complete virion formation.…”

Structural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes

“…The Rab family of small GTPases are fundamental to intracellular membrane trafficking in which organelles exchange proteins and lipids in an intricate network of vesicular transport. Furthermore, many viral and bacterial pathogens exploit Rabs for entry and survival [2][3][4][5][6] , and Rab misregulation is associated with human diseases such as neurodegeneration and cancer [7][8][9][10][11] . Rab5 is indispensable at early endosomes 12 , where it has a role in the activation of VPS34 13 .…”