Intracellular Trafficking of HBV Particles

Abstract

The human hepatitis B virus (HBV), that is causative for more than 240 million cases of chronic liver inflammation (hepatitis), is an enveloped virus with a partially double-stranded DNA genome. After virion uptake by receptor-mediated endocytosis, the viral nucleocapsid is transported towards the nuclear pore complex. In the nuclear basket, the nucleocapsid disassembles. The viral genome that is covalently linked to the viral polymerase, which harbors a bipartite NLS, is imported into the nucleus. Here, the partially double-stranded DNA genome is converted in a minichromosome-like structure, the covalently closed circular DNA (cccDNA). The DNA virus HBV replicates via a pregenomic RNA (pgRNA)-intermediate that is reverse transcribed into DNA. HBV-infected cells release apart from the infectious viral parrticle two forms of non-infectious subviral particles (spheres and filaments), which are assembled by the surface proteins but lack any capsid and nucleic acid. In addition, naked capsids are released by HBV replicating cells. Infectious viral particles and filaments are released via multivesicular bodies; spheres are secreted by the classic constitutive secretory pathway. The release of naked capsids is still not fully understood, autophagosomal processes are discussed. This review describes intracellular trafficking pathways involved in virus entry, morphogenesis and release of (sub)viral particles.

Early Steps of Hepatitis B Life Cycle: From Capsid Nuclear Import to cccDNA Formation

“…Moreover, it has been shown that the machinery involved in the endocytosis of epidermal growth factor receptor (EGFR), which acts as a cofactor for HBV entry, is also involved in the internalization and transport in the endosomal network of HBV [ 26 , 27 ]. The mechanisms leading to HBV escape from endosomes are not yet fully understood, and membrane fusion may be mediated by the fusogenic domains identified in the different surface proteins L, M, and S [ 7 , 28 ].…”

“…Upon infection, the rcDNA intermediate form is repaired so as to give rise to a complete double stranded covalently closed circular DNA (cccDNA) that is located in the nucleus and serves as a template for the transcription of all viral RNAs, including pgRNA [ 5 , 6 ]. In the cytoplasm, after reverse transcription, mature capsids containing rcDNA assemble with the viral envelope at the cellular multivesicular body, allowing for the formation and secretion of viral particles ( Figure 1 ) [ 7 , 8 , 9 ]. Alternatively, capsids can return directly to the nucleus, resulting in intracellular cccDNA amplification [ 10 , 11 ].…”

circDym prevents chronic neuropathic pain by competitive inhibition of Nlgn2 mRNA transport in neurites

“…It has been shown that circRNAs can competitively bind to microRNAs and RBPs, serving as RBP sponges and transporters for speci c molecules [33]. circRNAs have also been shown to be transported in exosomes by RBPs towards multivesicular bodies [34]. Related to our main objective, circDym, a conserved circRNA isoform derived from Dym, has been discovered to function as a microRNA sponge by binding to miR-9 and miR-346 and regulates protein synthesis [35].…”

Hepatitis B Virus Cure: Targets and Future Therapies

“…The most abundant viral antigen in the blood is HBsAg, which plays an important role in preventing immune control of HBV [ 8 , 30 ]. Circulating HBsAg is almost entirely in the form of non-infectious HBV subviral particles (SVPs) [ 31 , 32 , 33 ].…”

“…In the cytoplasm of HBV-infected hepatocytes, the nucleocapsid is transported through the nuclear pore complex by microtubule-mediated transport. Following capsid dissociation via unknown factors, rcDNA is released into the nucleus and is converted to cccDNA by host factors, forming a stable mini-chromosome [ 7 , 8 ]. The cccDNA is transcribed into pregenomic RNA (pgRNA), which is translated to the nucleocapsid protein and the HBV DNA polymerase and serves thereafter as the template for rcDNA synthesis.…”