Genomic analysis of the host response to hepatitis B virus infection

Abstract

Previous studies in hepatitis B virus (HBV)-infected humans and chimpanzees suggest that control of HBV infection involves the cells, effector functions, and molecular mediators of the immune response. The objective of the current study was to identify, in the liver of acutely HBV-infected chimpanzees, the spectrum of virus-induced and immune response-related genes that regulate the infection. The results demonstrate that HBV does not induce any genes during entry and expansion, suggesting it is a stealth virus early in the infection. In contrast, a large number of T cell-derived IFN-gamma-regulated genes are induced in the liver during viral clearance, reflecting the impact of an adaptive T cell response that inhibits viral replication and kills infected cells, thereby terminating the infection.

Fig. 1.

Course of acute HBV infection in chimpanzees after experimental i.v. inoculation of 10⁸ genome equivalents of HBV in week 0. (A) Ch1627 was also injected with an irrelevant control antibody in week 6. (B) Ch1615 was injected with a CD4-specific monoclonal antibody as described in the text. (C) Ch5835 did not receive any additional treatment. Intrahepatic HBV DNA (black squares) is expressed as a percentage (% max) of the peak HBV DNA levels in the liver of each animal (actual liver HBV DNA levels are presented in Table 2). Hepatitis B core antigen-positive (HbcAg) hepatocytes (gray bars) are expressed as percentage of the total number of hepatocytes. sALT (open circles) is expressed in units per liter. Intrahepatic expression profiles for IFN-γ, CD3, and 2′5′OAS were determined by RNase protection assay. Vertical arrows indicate the time of antibody injection. Stars indicate the time points for which gene expression profiling was performed.

Fig. 2.

Liver gene expression profile during acute HBV infection. (A) Genes correlated with viremia in all chimpanzees. No genes correlated positively or negatively with the level of intrahepatic HBV DNA during the time course of acute HBV infection in all three animals. (B) Liver gene expression profile associated with viral clearance in all three acutely HBV-infected chimpanzees. The gene identities are shown in Table 1 and the primary data in Tables 3 and 4. Green lines show the intrahepatic HBV DNA as a percentage (% max) of the corresponding peak levels. For optimal visualization, gene expression levels (red lines) are shown after normalization to the 10th and 90th percentiles for each gene. Values on the x axis represent weeks after inoculation with HBV.

Fig. 3.

Kinetics of liver gene expression during viral clearance in Ch1627. Early (blue), Middle (red), and Late (green) genes displayed maximal expression in weeks 12, 14, and 16, respectively.