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

乙肝病毒是人类的一种常见感染，全球有超过20亿人接触过这种病毒。大多数人从这种感染中完全康复，但有相当一部分人没有完全康复，成为病毒携带者，这种情况与后来的致命性肝硬变和肝癌有关。据估计，每年约有100万人死于乙肝病毒感染。在西方发达国家，有一种有效的疫苗，但在世界许多地区，这是不够的，因为那里可能有超过8%的人口是受感染的携带者。因此，需要设计新的抗病毒药物来抑制乙肝病毒感染，特别是使免疫系统可以看到病毒，以便从患者手中清除病毒。这就是我们应用的目标，这是基于我们最近的一项发现，该发现与以RNA为基因组核酸的这种病毒组装病毒颗粒的方式有关。我们发现，它们在这些RNA的序列和结构中编码了一个隐藏的说明手册，确保了传染性病毒粒子的快速和有效组装。乙肝病毒是一种有点不寻常的病毒，因为它最初围绕RNA前基因组RNA组装，但后来将其转化为病毒颗粒内的双链DNA版本。在广泛的初步实验中，我们已经表明，乙肝病毒很可能包含与其初始组装相同类型的说明手册。因此，应该可以使用药物来针对这一过程。我们正在申请为期两年的泵启动拨款，这将使我们能够更全面地研究这一机制，并开始筛选可能阻止组装的配体(药物)类型。在其他病毒系统中，这种药物导致部分组装，即它们产生免疫系统容易看到的非传染性但高度免疫原性的病毒版本。我们在这里获得的信息在未来与制药公司就开发新的抗乙肝药物进行讨论时将是非常宝贵的。

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.