The roles of the pre-genomic RNA in Hepatitis B Virus nucleocapsid assembly.

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Hepatitis B virus is a common infection in humans with over 2 billion people worldwide having been exposed to the virus. The majority of people recover fully from such infections but a significant minority do not, becoming carriers of the virus, a condition linked to later lethal cirrhosis and liver cancer. It is estimated that ~1 million people die every year as a result of HBV infection. In advanced western countries there is an effective vaccine, but this is not sufficient in many parts of the world where over 8% of the population may be infected carriers. As a result there is a need to devise novel anti-viral drugs that would inhibit HBV infections, and in particular render the virus visible to the immune system so that it can be cleared from patients. This is the goal of our application, which is based on a recent discovery we made relating to the way that such viruses having RNA as their genomic nucleic acid, assemble their viral particles. We have discovered that they encode a hidden instruction manual in the sequence and structure of these RNAs that ensures rapid and efficient assembly of infectious virions. HBV is a slightly unusual virus because it assembles initially around an RNA pregenomic RNA but later converts that to a double-stranded DNA version within the viral particle. In extensive preliminary experiments we have shown that HBV may well contain the same sort of instruction manual for its initial assembly. It should therefore be possible to target this process using drugs. We are asking for a two year pump-priming grant that will allow us to investigate this mechanism more comprehensively and begin to screen for the types of ligands (drugs) that could block assembly. In other viral systems, such drugs lead to partial assembly, that is they create non-infectious but highly immunogenic versions of the virus that are readily seen by the immune system. The information we gain here will be invaluable in future discussions with drug companies about developing novel anti-HBV therapy.