Immune selection during chronic hepadnavirus infection
Late-stage outcomes of chronic hepatitis B virus (HBV) infection, including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) result from persistent liver injury mediated by HBV antigen specific cytotoxic T lymphocytes (CTLs). Two other outcomes that often accompany chronic infection, the emergence of mutant viruses, including HBe-antigen negative (HBeAg (−)) HBV, and a reduction over time in the fraction of hepatocytes productively infected with HBV, may also result from persistent immune attack by antiviral CTLs. To gain insights into how these latter changes take place, we employed computer simulations of the chronically infected liver.
Computational programs were used to model the emergence of both virus-free hepatocytes and mutant strains of HBV.
The computer modeling predicted that if cell-to-cell spread of virus is an efficient process during chronic infections, an HBV mutant that replicated significantly more efficiently than the wild type would emerge as the prevalent virus in a few years, much more rapidly than observed, while a mutant that replicated with the same or lower efficiency would fail to emerge. Thus, either cell-to-cell spread is inefficient or mutants do not replicate appreciably more efficiently than wild type. In contrast, with immune selection and a higher rate of killing of hepatocytes infected with wild-type virus, emergence of mutant virus can be explained without the need for a higher replication rate. Immune selection could also explain the emergence of virus-free hepatocytes that are unable to support HBV infection, since they should have a lower turnover rate than infected hepatocytes.
KeywordsChronic hepatitis B Immune selection HBeAg (−) HBV Hepatocyte clones
- 17.Seeger C, Zoulim F, Mason WS (2006) Hepadnaviruses. In: Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B, Straus SE (eds) Fields virology, 5th edn. pp 2977–3029.Google Scholar
- 27.Kojima M, Udo K, Takahashi Y, Yoshizawa H, Tsuda F, Itoh Y, et al. Correlation between the titer of antibody to hepatitis B core antigen and presence of viral antigens in the liver. Gastroenterol 1977;73:664–7.Google Scholar
- 33.Jilbert AR. Studies of the pathogenesis of hepadnavirus infection (PhD thesis). Adelaide: University of Adelaide; 1989.Google Scholar
- 38.Radaeva S, Li Y, Hacker HJ, Burger V, Kopp-Schneider A, Bannasch P. Hepadnaviral hepatocarcinogenesis: in situ visualization of viral antigens, cytoplasmic compartmentation, enzymic patterns, and cellular proliferation in preneoplastic hepatocellular lineages in woodchucks. J Hepatol 2000;33:580–600.PubMedCrossRefGoogle Scholar