De novo synthesis of hepatitis B virus nucleocapsids is dispensable for the maintenance and transcriptional regulation of cccDNA

Abstract

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Hepatitis B Virus DNA Integration: In Vitro Models for Investigating Viral Pathogenesis and Persistence

“…HBV integration was shown to occur in patients in all phases of chronic infection [ 77 , 78 ], in acute infection [ 79 ] and in children [ 80 , 81 ]. Moreover, in vivo (woodchuck and duck models of HBV infection [ 34 , 82 ]) and in vitro HBV models showed that integration occurs within days [ 48 , 51 ] (on the order of tens of minutes by some reports [ 83 ]).…”

“…While stable cell lines that overexpress HBV can force new DNA integrations [ 52 , 53 ], integration does not seem to occur continuously in a persistently-infected cells. In vitro HBV infection models have shown that integration is not affected by inhibition of reverse transcription (e.g., from nucleoside analogue treatment [ 48 ]) and requires neither de novo HBV replication [ 51 ] nor viral proteins of the incoming virus [ 62 ]. Together, this suggests that integration occurs at the initial infection and that additional integration events as results are due to new infection events or clonal expansion.…”

“… The virus infects the whole liver following the initial infection. In this initial phase, the majority of HBsAg is derived from cccDNA, as integrated HBV DNA is rare (1 integration per ~10,000 cells, as shown in in vitro [ 48 , 51 ] and in vivo models). Ongoing nuclear import and integration in chronically-infected cells is rare [ 48 , 49 , 50 , 51 ], so integration rate remains relatively stable.…”

“…Conversely, nuclear introduction of large numbers of HBV DNA molecules (via over-expressing constructs or transfection) can drive relatively high integration rates, allowing easy study of the integration process. However, this does not reflect a true infection; nuclear import of new HBV virions occurs relatively inefficiently in HBV infection [ 48 , 49 , 50 , 51 ], so levels of HBV DNA in infected hepatocytes is relatively low. Newly-developed infection models expressing the HBV receptor have solved this to some degree by largely recapitulating the virological aspects accurately.…”

Celebrating the third year of JHEP Reports in the COVID-19 era

“…On multivariate analysis, women were not more likely to die on the waiting list than men and their chances of undergoing liver transplant were similar to those of men. In another study, Tu et al 12 investigated the role of de novo nucleocapsid formation on cccDNA maintenance and transcriptional regulation, taking advantage of an HBc defective virus. They report that de novo HBV core protein produced from cccDNA is not required to maintain cccDNA copy numbers during long-term in vitro infection.…”