Hepadnaviruses are a family of DNA viruses that infect the liver of their host. This family has five well-characterized members that infect different birds and mammals (for reviews, see Ganem, 1996; Seeger and Mason, 2000). Human hepatitis B virus (HBV) is the prototype mem- ber of this family. Other members include woodchuck hepatitis virus (WHV), ground squirrel hepatitis virus (GSHV), duck hepatitis B virus (DHBV), and heron hepatitis B virus (HHBV). The hepadnaviruses can cause either transient or persistent infections. In humans, transient in- fections are cleared within several months, while persistent infections are generally lifelong. The host immune response is a key determinant in the ultimate fate of the hepadnavirus infection. Chronic infections with HBV, WHV, and GSHV are associated with increased incidences of hepatocellular carcinoma (HCC). In fact, HBV is the leading cause of liver cancer worldwide (Beasley, 1988; also see Chapter 12).
The DNA genome of hepadnaviruses is only ~3 kb. Within the virus particle the DNA is in a relaxed circular conformation. Although they contain DNA, hepadnaviruses replicate via re- verse transcription of an RNA intermediate (Summers and Mason, 1982). Even though retro- viruses also replicate via reverse transcription, there are fundamental differences between the pathways employed by the two virus families. One difference is that hepadnaviruses do not have an integration step in their life cycle. Instead, hepadnaviruses maintain their genomes as a co- valently closed, circular DNA in the nucleus.
As mentioned above, infection with the mammalian hepadnaviruses can lead to the devel- opment of HCC. In these liver tumors, it is common to find integrated pieces of hepadnaviral DNA even though hepadnaviruses do not have an obligate integration step in their life cycle. These findings raise the question whether DNA integration plays a role in the development of liver cancer. The answer is yes and no. Infection of woodchucks with WHV results in the devel-opment of hepatocellular carcinoma, with frequencies approaching 100% after 2 years. In a large percentage of liver tumors from infected animals, WHV DNA is found integrated near a member of the myc oncogene family, N-myc (Fourel et al., 1990, 1994). The integrated WHV DNA is thought to result in increased expression of the neighboring myc locus. This insertional activation of the myc oncogene locus contributes to the development of the cancer. As illuminat- ing as the WHV story has been, HBV-induced tumors do not seem to result from insertional activation of a common oncogene. For HBV-induced liver cancers, a popular explanation is the “indirect model” (Ganem, 1996), which states that HBV, its genes, and their products make no direct contribution to transformation. Instead, HBV-induced liver injury, which is mediated by the host immune response, ultimately leads to liver cancer. During chronic infection, a persistent low level of liver damage is continuously occurring via the immune response. This immune re- sponse, which is not vigorous enough to clear the infection, is responsible for the hepatitis. In these individuals, the immune response leads to killing of infected cells. To replace the cells that die, the rate of hepatocyte proliferation increases, with a concomitant increase in the frequency of mutations. In humans, liver cancer develops after 20 to 40 years of chronic infection (Chapter12). During this long latency period, the appropriate constellation of mutations accumulates, re- sulting in the development of HCC. In spite of the popularity of the above model, it should be emphasized that it is currently not well understood how HBV infection leads to the development of HCC. It is possible that HBV contributes to HCC by multiple mechanisms, both direct and indirect.