Hepatitis B virus: significance of naturally occurring mutants

Mutations of viral genomes are normal biological events and result in the coexistence of viral genotypes in infected individuals ('quasispecies'). Hepatitis B virus (HBV) and the related animal hepadnaviruses have a mutation rate which is intermediate between DNA and RNA viruses because they replicate asymmetrically via reverse transcription of an RNA intermediate. HBV mutants affecting all known reading frames of the viral genome have been demonstrated in patients with acute fulminant or chronic HBV infection. Some of the mutations identified to date suggest a contribution to viral latency, low level HBV infection, the severity of liver disease and vaccine escape. Since most viral genomes carry more than one mutation and most individuals are infected by more than one variant, the demonstration of a causal relationship between a single mutation and a biological or pathobiological effect requires the in vitro and in vivo analysis of genetically defined mutants. Such analyses should allow a molecular understanding of the genetic contribution of HBV to the variable natural course of HBV infection, ranging from an asymptomatic healthy carrier state to acute or even fulminant hepatitis, chronic liver disease, liver cirrhosis and hepatocellular carcinoma.