Hepatitis B pre-genome RNA may promote nucleocapsid assembly

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Researchers from the University of York and the University of Leeds (both UK) have uncovered a stage in hepatitis B replication, in which an RNA signal promotes nucleocapsid assembly. They hypothesize that interrupting this mechanism could pave the way for new treatments.

Formation of the hepatitis B virus is an essential stage of the life-cycle; however, it has previously been poorly understood. In this study, published recently in Nature Microbiology, the team discovered a sequence-specific interaction between pre-genome RNA and hepatitis B proteins that appeared to play a key role in nucleocapsid assembly.

The researchers used both RNA SELEX and bioinformatics to identify regions in the hepatitis B pre-genomic RNA that had high affinity for core protein dimers. They demonstrated these RNAs triggered sequence-specific assembly of virus-like particles via the formation of RNA stem–loops. The team further demonstrated that, when compared with an absence of RNA, the pre-genome RNA allowed the process to occur with increased fidelity and yield.

In addition, the researchers carried out biophysical assays, which indicated interactions between RNA and core proteins, suggesting that RNA–protein complexes may play a role in regulating organization of pre-genome nucleocapsid assembly.

There is currently a lack of effective treatment for hepatitis B, and these findings could present a new avenue for drug development. The researchers are currently collaborating with the National Institutes of Health (MD, USA) to identify drug candidates that disrupt this stage in the hepatitis B life-cycle.

Author Peter Stockley (University of Leeds) concluded: “There is a vaccine for the virus, but once you have the condition there is no treatment, other than drugs that can reduce symptoms but not change the long-term outlook.

“We often compare the disease to HIV due to the way in which the virus is passed from person-to-person, but unlike HIV there are no effective drugs to improve quality of life outcomes.  Now that we know how the virus assembles, we can interrupt the interactions with the RNA signals.”

Sources: Patel N, White SJ, Thompson RF et al. HBV RNA pre-genome encodes specific motifs that mediate interactions with the viral core protein that promote nucleocapsid assembly. Nat. Microbiol. 2(17098), doi:10.1038/nmicrobiol.2017.98 (2017); www.york.ac.uk/news-and-events/news/2017/research/scientists-step-closer-to-drug-treatment-hepatitis/

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