Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA

Robert E. Lanford, Zongdi Feng, Deborah Chavez, Bernadette Guerra, Kathleen M. Brasky, Yan Zhou, Daisuke Yamane, Alan S. Perelson, Christopher M. Walker, Stanley M. Lemon

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

Hepatitis A virus (HAV) is an hepatotropic human picornavirus that is associated only with acute infection. Its pathogenesis is not well understood because there are few studies in animal models using modern methodologies. We characterized HAV infections in three chimpanzees, quantifying viral RNA by quantitative RT-PCR and examining critical aspects of the innate immune response including intrahepatic IFN-stimulated gene expression. We compared these infection profiles with similar studies of chimpanzees infected with hepatitis C virus (HCV), an hepatotropic flavivirus that frequently causes persistent infection. Surprisingly, HAV-infected animals exhibited very limited induction of type I IFN-stimulated genes in the liver compared with chimpanzees with acute resolving HCV infection, despite similar levels of viremia and 100-fold greater quantities of viral RNA in the liver. Minimal IFN-stimulated gene 15 and IFIT1 responses peaked 1-2 wk after HAV challenge and then subsided despite continuing high hepatic viral RNA. An acute inflammatory response at 3-4 wk correlated with the appearance of virus-specific antibodies and apoptosis and proliferation of hepatocytes. Despite this, HAV RNA persisted in the liver for months, remaining present long after clearance from serum and feces and revealing dramatic differences in the kinetics of clearance in the three compartments. Viral RNA was detected in the liver for significantly longer (35 to >48 wk) than HCV RNA in animals with acute resolving HCV infection (10-20 wk). Collectively, these findings indicate that HAV is far stealthier than HCV early in the course of acute resolving infection. HAV infections represent a distinctly different paradigm in virus - host interactions within the liver.

Original languageEnglish (US)
Pages (from-to)11223-11228
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number27
DOIs
StatePublished - Jul 5 2011
Externally publishedYes

Keywords

  • Immune evasion
  • Innate immunity
  • Viral persistence

ASJC Scopus subject areas

  • General

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