Chronic HCV Infections in Chimpanzees
Gene Expression in Chimpanzees with Chronic HCV Infection
To analyze the changes in gene expression accompanying long term chronic
infection, DNA microarray analyses were conducted on liver from ten chimpanzees
persistently infected with HCV. The infected livers were compared to six
baseline samples comprised of 4 individual animals, a pool of 3 animals and a
pool of 9 animals. A total of 162 genes were differentially regulated in
chronically infected animals in comparison to uninfected controls. Many genes
exhibited a remarkable consistency in changes in expression in the ten
chronically infected animals. A second method of analysis identified 971 genes
altered in expression during chronic infection at a 99% confidence level (see
Table 4 and heat map). As with acute-resolving HCV infections, many interferon
(IFN)-stimulated genes (ISGs) were transcriptionally elevated, suggesting an
ongoing response to IFN and/or double-stranded (ds) RNA which is amplified in
downstream ISG expression. A model was developed based on the data from multiple
systems that predicts that a low percentage of hepatocytes are infected in the
liver during acute and chronic infections, because the secretion of IFN results
in zones of resistant hepatocytes and loss of available replication space in the
liver. See accompanying manuscript for full discussion of models.
Table 1. Genes
upregulated during persistent HCV infection. Genes (134) that were
elevated 2.0 fold or greater in at least 5 of the 10 HCV-infected animals in
comparison to all 6 baselines are included. The animal identification number is
given at the top, and the gene name is indicated at the left and gene function
is given at the right. Section 1 includes 39 genes that exhibited changes in all
ten animals, with each subsequent section (separated by heavy lines)
representing genes with changes in progressively fewer animals. Genes in each
section are listed according to the magnitude of the average expression change
with the average being calculated from all 10 animals, even when all 10 did not
exhibit a FC >2.0. [Download excel
table]
Table 2. Genes
downregulated during persistent HCV infection. Genes (59) that were
decreased by -2.0 fold or more in 5 of the 10 of the animals in comparison to
all 6 baselines are included. Section 1 includes 6 genes that exhibited changes
in all ten animals, with each subsequent section representing genes with changes
in progressively fewer animals. Genes in each section are listed according to
the magnitude of the average expression change with the average being calculated
from all 10 animals, even when all 10 did not exhibit a FC >2.0. The animal
identification number is given at the top, and the gene name is indicated at the
left and the function is given on the right. [Download
excel table]
Table 3. Genes altered in
expression during HCV infection by ANOVA. A total of 971 genes were An
independent analysis was performed using a different approach. Initially, two
sets of filtering were performed: genes absent in all samples were omitted and
genes with a FC of <2.0 in all possible pairwise combinations were removed. A
list of 2110 genes was generated at the 95% confidence level and 971 genes at
the 99% confidence level. [Download
excel table]
Figure 1. Hierarchical clustering of genes with altered expression
during HCV infection. A heat map is shown illustrating 2-dimensional
hierarchical clustering of 971 genes identified as differentially regulated in
infected vs. noninfected animals by ANOVA at a 99% confidence level. Animals
with HCV infection cluster separately from animals without HCV infection (top
cluster diagram). Genes increased or decreased during HCV infection cluster
separately (cluster diagram to left). Increased and decreased expression of
specific genes is illustrated by red and green, respectively, while black
indicates no change. [click
here to see larger version]
