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Journal of Virology, August 2001, p. 7059-7066, Vol. 75, No. 15
Department of Virology and
Immunology1 and Department of Laboratory
Animal Medicine,2 Southwest Regional Primate
Research Center, Southwest Foundation for Biomedical Research, San
Antonio, Texas 78227
Received 21 February 2001/Accepted 25 April 2001
Hepatitis C virus (HCV) poses a worldwide health problem in that
the majority of individuals exposed to HCV become chronically infected
and are predisposed for developing significant liver disease. DNA
microarray technology provides an opportunity to survey transcription
modulation in the context of an infectious disease and is a
particularly attractive approach in characterizing HCV-host
interactions, since the mechanisms underlying viral persistence and
disease progression are not understood and are difficult to study.
Here, we describe the changes in liver gene expression during the
course of an acute-resolving HCV infection in a chimpanzee. Clearance
of viremia in this animal occurred between weeks 6 and 8, while
clearance of residual infected hepatocytes did not occur until 14 weeks
postinfection. The most notable changes in gene expression occurred in
numerous interferon response genes (including all three classical
interferon antiviral pathways) that increased dramatically, some as
early as day 2 postinfection. The data suggest a biphasic mechanism of
viral clearance dependent on both the innate and adaptive immune
responses and provide insight into the response of the liver to a
hepatotropic viral infection.
Approximately 3% of the worldwide
population is persistently infected with hepatitis C virus (HCV)
(3). Although chronic HCV infections are often clinically
silent for decades, an estimated 20% of persistently infected
individuals will develop serious liver disease, including cirrhosis and
liver cancer (2, 3). Currently no vaccine is available,
and antiviral therapy is limited to alpha interferon (IFN- DNA microarrays provide a powerful technique for exploring the myriad
of changes in gene expression characteristic of various physiological
and pathological conditions. Microarray technology has been used in a
variety of systems, including studies in whole organisms (40,
60). To date, microarray studies involving viral infections
(e.g., human immunodeficiency virus, human cytomegalovirus, and human
papillomavirus) (13, 28, 63) have been restricted to
tissue culture models. These systems provide a controlled environment for analysis of virus-host interactions, although they occur in the
absence of the immune response. In this study, we anticipated four
types of changes in gene expression within the liver as a consequence
of HCV infection: (i) changes due to the endogenous antiviral response
of the liver (e.g., induction of IFN- Chimpanzee.
The chimpanzee was housed at the Southwest
Regional Primate Research Center at the Southwest Foundation for
Biomedical Research. The animal was cared for by members of the
Department of Laboratory Animal Medicine in accordance with Guide
for the Care and Use of Laboratory Animals (16a), and all
protocols were approved by the Institutional Animal Care and Use
Committee. Chimpanzee 4x0271 was inoculated intravenously with
chimpanzee serum containing 1.5 × 107 genome
equivalents (ge) of HCV genotype 1a, H77 strain (6, 8,
50). Serum and liver needle biopsies were taken through the
course of infection. Liver biopsies were obtained early in the morning
under fasting conditions to avoid postprandial changes in liver metabolism.
ALT, antibody, and TaqMan analyses.
Total RNA prepared from
liver biopsies was used to perform microarray analyses and to monitor
viral RNA levels by quantitative reverse transcriptase-PCR (RT-PCR)
(37). Serum samples were taken to monitor viral RNA
levels, changes in serum alanine transaminases (ALT), and antibody
response to HCV proteins (ELISA [enzyme-linked immunosorbent assay]
Testing System 3.0; Ortho Diagnostic Systems, Raritan, N.J.). HCV RNA
was quantified by a real-time, 5' exonuclease RT-PCR (TaqMan) assay
using an ABI 7700 sequence detector (PE Biosystems, Foster City,
Calif.). The primers and probe were derived from the conserved region
of the 5' noncoding region and were selected using the Primer Express
software designed for this purpose (PE Biosystems). The forward primer
was from nucleotides 149 to 167 (5'-TGCGGAACCGGTGAGTACA-3'),
the reverse primer was from nucleotides 210 to 191 (5'-CGGGTTTATCCAAGAAAGGA-3'), and the probe was from nucleotides 189 to 169 (5'-CCGGTCGTCCTGGCAATTCCG-3'). The
fluorogenic probe was labeled with 6-carboxyfluorescein and
6-carboxytetramethylrhodamine and was obtained from Synthegen (Houston,
Tex.).
Microarray analysis.
All RNA and DNA preparations were made
according to Affymetrix (Santa Clara, Calif.) protocols, and
hybridizations and data analyses were also performed using Affymetrix
protocols, equipment, and software. Briefly, liver punch biopsies from
days 0, 2, and 7 and weeks 2, 4, 6, 8, and 14 were homogenized and
processed for total RNA using TRIZOL (Life Technologies, Gaithersburg,
Md.). These time points were chosen to analyze changes in liver gene expression during the very early stages of viral infection and during
peaks in viremia and ALT. Total liver RNA was further purified using an
RNeasy total RNA isolation kit (Qiagen, Valencia, Calif.); cDNA
synthesis reactions were carried out with 20 µg of total RNA, using
Superscript Choice system (Life Technologies) with an oligo (dT) primer
containing a T7 RNA polymerase promoter (Research Genetics, Huntsville,
Ala.). Following second-strand synthesis, the reaction mixture was
extracted with phenol-chloroform-isoamyl alcohol, and double-stranded
cDNA was ethanol precipitated. The DNA was resuspended in RNase-free
water and used to synthesize biotinylated cRNA using a BioArray
high-yield RNA transcription labeling kit (ENZO Diagnostics,
Farmingdale, N.Y.). Biotinylated cRNA was purified using RNeasy
affinity columns (Qiagen). Fragmentation and hybridizations to
Affymetrix HumanFL microarrays were performed by Research Genetics.
Data analysis was facilitated by the GeneChip expression analysis
sequence information database (Affymetrix).
To initiate this study, a young adult male chimpanzee, not
previously exposed to infectious agents, was inoculated with the genotype 1a, H77 strain of HCV (1.50 × 107 ge)
(6, 7, 49). The animal experienced a rapid viral clearance
profile (Fig. 1). Viremia was first
detected by day 2 postinoculation (p.i.) at 2 × 104
ge/ml of serum, peak serum titers occurred at week 4 (4.5 × 105 ge/ml), and viremia was no longer detectable by week 8. A similar profile was observed for viral RNA in the liver; a 3-log
decline in liver viral RNA levels occurred between weeks 6 and 8, concomitant with the loss of viremia at week 8; however, residual viral
RNA persisted in the liver until week 14 p.i. Seroconversion for
anti-HCV antibodies occurred between weeks 6 and 8, as well. Serum ALT levels rose sharply between weeks 4 and 6 and declined between weeks 6 and 8 coincident with viral clearance and seroconversion (Fig. 1). The
delay in complete clearance of viral RNA from the liver suggests that
different mechanisms may be operative between inhibition of replication
and subsequent clearance of viremia and the clearance of residual
infected hepatocytes.
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.15.7059-7066.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
DNA Microarray Analysis of Chimpanzee Liver during
Acute Resolving Hepatitis C Virus Infection
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results and Discussion
References
INTRODUCTION
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Abstract
Introduction
Materials and Methods
Results and Discussion
References
) and
ribavirin, which afford viral clearance in a minority of cases
(1). HCV persists despite the presence of specific humoral
and cellular immune responses, and little is understood with regard to
the factors leading to viral clearance or persistence, yet early events
in the acute infection probably influence the outcome (12, 16,
17, 23, 39). These events are difficult to examine in human
populations, since the time of infection is rarely known and access to
serial liver samples is constrained. Most immunological studies of HCV infection understandably involve chronically infected patients and thus
are directed more at disease manifestations than at events leading to
viral persistence. The chimpanzee model is particularly attractive for
the analysis of the factors involved in viral clearance, since greater
than 60% of inoculated animals rapidly clear the infection (6,
7, 36). These same factors may lead to rapid viral clearance in
humans; however, the identification and analysis of individuals at the
time of exposure is difficult. We have chosen to use DNA microarrays as
a method to probe the liver for changes in gene expression associated
with resolution of an HCV infection in a chimpanzee.
and IFN-
response genes),
(ii) changes due to the innate and adaptive immune response to the
infection (e.g., activation and infiltration of NK cells, macrophages,
and lymphocytes), (iii) changes due to the hepatocyte response to the
cytokines expressed by these cells, and (iv) changes due to
interactions between the hepatocyte and HCV proteins. Ultimately, we
expect that some of these changes may become predictive of viral
clearance or persistence.
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results and Discussion
References
RESULTS AND DISCUSSION
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Abstract
Introduction
Materials and Methods
Results and Discussion
References
View larger version (32K):
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FIG. 1.
HCV infection profile of the chimpanzee used in DNA
microarray studies. Chimpanzee 4x0271 was inoculated with HCV genotype
1a, H77 strain, and serial serum and liver biopsy samples were obtained
during the course of infection. Serum ALT values were measured as an
indication of liver damage ( 
; horizontal line indicates upper limit
of normal). Quantitative RT-PCR (TaqMan) values for viral RNA in the
serum or liver are given as genome equivalents per milliliter of serum
(shaded bars) or micrograms of total liver RNA (unshaded bars),
respectively. Seroconversion for anti-HCV antibodies was monitored by
third-generation ELISA (+ and 
). d, day.
Microarray analyses were performed using the Affymetrix HumanFL DNA
microarrays which contain oligonucleotides representing approximately
7,000 human genes. Transcripts from approximately one-third (2,300) of
the genes on the microarray were detected at each time point and are
probably well representative of the total gene expression of the liver.
Samples from days 2 and 7 and weeks 2, 4, 6, 8, and 14 were compared to
day 0 samples, and only those genes that had a fold change (FC) in
expression of 
3.5 were included in this analysis (the baseline cutoff
for Affymetrix HumanFL microarrays is actually a twofold change).
Several important aspects of the data were immediately apparent. First,
relatively few changes (14 genes) were observed on day 2 (Table
1; seven are listed in Fig.
2), indicating that changes in liver gene
expression unrelated to HCV did not present a problem with the assay.
This was of concern due to the potential of the mammalian liver to undergo dramatic changes in gene expression in response to the environment (e.g., postprandial metabolic changes). Second, most of the
genes with altered expression were detected in more than one sample
(Fig. 2), again arguing against spurious changes. FC of 3.5 were
observed for 327 genes (222 prior to clearance of viremia); of these,
162 were altered in expression in more than one time point. The
majority of genes with FC of 3.5 at a single time point occurred at
weeks 6 (32%) and 14 (47%); however, many of these single time point
changes at the 3.5-fold cutoff level exhibited FC between 3.0 and 3.4 in adjacent time points.
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Of the 327 genes that experienced FC of 3.5, 139 genes exhibited FC
of 5 to 10, 37 genes exhibited FC of 10 to 20, 14 genes exhibited FC of
20, and 3 genes exhibited FC of 90 (Table 1; Fig. 2). Last,
clearance of viremia at week 8 was accompanied by a decline to baseline
levels for the majority of genes with altered expression levels,
especially the IFN response genes (Fig. 2, p15/17 and MK [Midkine]).
For evaluation purposes, these genes were divided into functional
groupings, and 116 are depicted in Fig. 2 (a complete data set can be
viewed at
www.sfbr.org/sfbr/departments/virology/hepatitis.html).
IFN response.
Thirty-three of the genes that exhibited a fold
change in expression by microarray analysis are known IFN response
genes (22) (red type in Fig. 2), and 5 of the 14 genes
exhibiting changes in expression at day 2 were IFN-inducible genes.
Most changes at this early time point probably reflect a response to
IFN-/
secreted by infected hepatocytes. Although changes in
expression of the IFN genes themselves were not detected, if a
relatively small percentage of hepatocytes were infected (see below),
IFN induction may be below the level of detection. However, even low levels of IFN can result in substantial amplification of IFN response genes in adjacent, uninfected cells. For example, two of the genes (p15/17 [22] and p27 [21]) with FC of
90 are IFN- response genes. MK, a third gene up-regulated
>90-fold, is a retinoic acid response gene that plays a role in
inflammation and angiogenesis (55). MK probably is
regulated also by IFN-, given that considerable cross-talk exits
between the IFN and retinoic acid pathways (14). MK and
p15/17 encode cytokines that are chemotatic for neutrophils and enhance
the proliferation and cytolytic activity of NK cells, respectively
(21, 55).
/ or IFN-) are operative over time. The mechanisms
regulating these distinct expression patterns are not understood, but
evidence suggests that the IFN-/ antiviral response is certainly
complex and constitutes more than the classically defined antiviral
pathways of 2',5'-oligoadenylate synthetase (OAS), double-stranded
RNA-dependent protein kinase R (PKR), and the Mx genes. Indeed,
numerous IFN- genes have been described, and the roles of many of
these in antiviral responses have yet to be defined (22).
|
[ISG15] and 
[16-Jun]), genes with a late peak in expression level (
[MK]), and genes with an intermediate pattern in which
maximum levels were reached early and were sustained (X [p27]). d,
day.
Cytokines and growth factors.
Other cytokine or
immunomodulatory genes that were upregulated in liver tissue (Fig. 2)
included macrophage inhibitory cytokine 1 (MIC-1), macrophage
inflammatory protein 1 beta (MIP-1), macrophage chemoattractant
protein 1 (MCP-1), IP-10, platelet derived endothelial cell growth
factor/thymidine phosphorylase (PD-ECGF/TP), and Mac-2-binding protein
(Mac2BP). Generally, these gene products have been shown to be
chemotactic and/or stimulatory to various immune cells. For example,
MIC-1 is a distant member of the transforming growth factor superfamily of genes that may serve as an autocrine inhibitor of
macrophage activation (11). The chemokines MCP-1,
MIP-1, and IP-10 are important in recruitment and stimulation of
monocytes, macrophages, dendritic cells, NK cells, and T lymphocytes
(5, 53). PD-ECGF/TP is functionally diverse, promoting
chemotaxis of endothelial cells, angiogenesis, and regulation of
steady-state levels of thymidine within cells, and is IFN inducible
(43). Mac-2BP is a multifunctional protein important in
cell adhesion and interaction with extracellular matrix proteins,
stimulation of NK cell activity, and production of interleukin-1 (IL-1)
and IL-6 by monocytes (52). Assigning specific functions
for these cytokines with regard to HCV infection requires further investigation.
Gene regulation and cell replication. Many genes encoding DNA-binding proteins and transcription factors changed in expression throughout the infection. Specific increases in mRNAs encoding proliferating cell nuclear antigen (PCNA), histones, and cyclin genes (Fig. 2) indicated the presence of proliferative changes in the liver, which may result from liver regeneration to replace damaged hepatocytes and other liver-specific cells. These increases coincided with peak ALT levels (Fig. 1).
Genes encoding transcription factors involved in generating the IFN response were increased in expression, including signal transducer and activator of transcription 1 (STAT1) and IFN regulatory factor 7 (IRF-7) (Fig. 2). STAT1 is a member of a family of latent, cytosolic transcription factors activated and/or up-regulated by a variety of stimuli (prolactin, MK, IFN-/, and IFN-) (20, 41,
51). Upon activation, STAT1 forms hetero- or homodimers, translocates to the nucleus, and mediates transcription of various genes, including IFN response genes (e.g., IRF-1) (41,
54). STAT1 encodes two splice variants, STAT1 and STAT1.
The latter is a dominant-negative form of the protein that binds DNA
but cannot activate transcription (41, 54). In this study
STAT1 mRNA increases were greater than for STAT1. This disparity
may reflect the in vivo levels of the transcripts in hepatocytes
following IFN activation, or STAT1 may be important in regulating
STAT1 activity following activation and induction by IFNs or other
cytokines (e.g., MK) (51). IRF-7 is a multifunctional gene
product that is transcriptionally activated in virus-infected cells and
is a key player in transactivating downstream IFN- genes (44, 45). Ironically, IRF-7 also functions as a transcriptional
repressor of IRF-1 in Epstein-Barr virus-infected cells
(62).
Other up-regulated immune transcription factors in this study included
stimulated trans-acting factor of 50 kDa (STAF50) and IFN-inducible protein 16 (IFI-16). STAF50 is the human counterpart to
the mouse Rpt-1 (regulatory protein, T-lymphocyte 1) gene that has been
shown to negatively regulate the IL-2 receptor gene (57). IFI-16 encodes an IFN- response gene that also can function as a
repressor of transcription (33). The roles of these gene
products during the acute stages of HCV infection remain to be
determined, especially since several of these genes function as
transcriptional repressors. Two central players in activating
downstream IFN response genes, p48 of IFN-stimulated gene factor 3 (ISGF3) (complex of STAT1 -STAT2-p48) and IRF-1 (44, 47,
54) did not change in expression levels throughout the study
beyond baseline levels (twofold change). The IRF-1 expression profile
seen by microarray analysis was confirmed by quantitative RT-PCR
(TaqMan) analysis (data not shown). That IRF-1 is required for
activation of NK cells and that the liver contains a significant
population of resident NK cells raises an interesting question as to
whether HCV partially avoids aspects of the IFN response by
circumventing up-regulation of ISGF3 and IRF-1 by as yet unknown
mechanisms (9, 24). The likelihood also exists that the
IFN response to HCV infection in the liver does not require expression
of these specific gene products. Small increases in IRF-1 or p48 not
considered significant by microarray analysis still may be biologically
relevant in the immune response to this virus. The fact that the
IFN-/ response was demonstrable by increases in
IFN-/-inducible genes and not by increases in the IFN-/
genes themselves supports this supposition.
Immune cell markers.
Several immune cell markers (e.g., CD18
and CD38) (Fig. 2) were detected at the later time points, possibly
indicating an immune cell infiltrate. However, increases in
T-cell-specific markers (e.g., CD3, CD4, and CD8) remained essentially
unchanged, with the exception of an increase in the T-cell receptor
(TCR) chain at week 14 (Fig. 2). Genes encoding major
histocompatibility complex (MHC) class II and proteasome components
were also up-regulated during the later time points of infection,
further suggesting an immune cell infiltrate, although liver-specific
endothelial cells also express MHC class II (35). Since
the liver participates in clearance of activated T cells from the
circulation (19), small increases due to HCV-specific
lymphocytes might not be detected above the baseline. The apparent lack
of a measurable lymphocytic infiltrate by microarray analysis is,
however, consistent with our histopathological findings from numerous
HCV-infected chimpanzees. The majority of HCV-infected animals do not
exhibit significant inflammatory lesions during the acute phase of
infection, and the histopathology typically involves hepatocyte
swelling with disruption of the sinusoidal spaces that returns to
normal following viral clearance. Occasionally, isolated lymphocytic
infiltration in portal areas is noted. The hepatocyte swelling appears
to involve all hepatocytes, suggesting that the observed histological
changes are in response to IFN or other cytokines, since our
calculations suggest that not all hepatocytes are infected during the
acute phase (see below). Importantly, the apparent minimal T-cell
response in this animal occurred in the presence of high levels of
IP-10 (FC of >50 for weeks 4 to 6), which is chemoattractant for
liver-infiltrating lymphocytes in hepatitis. Other immunomodulatory
genes (e.g., immunophilins FKBP54 and FKBP12, lipocalin) exhibited peak
expression levels between weeks 4 and 8 (Fig. 2) and probably reflect
activation of NK cells, Kupffer cells, and other polymorphonuclear cells.
Apoptosis. Genes involved in apoptosis in other systems (e.g., tumor necrosis factor [TNF]-related apoptosis-inducing ligand (TRAIL), TNF receptor [TNFR], and FAS/APO-1) (15, 59, 61) were up-regulated as early as day 7. Apoptosis of infected hepatocytes may be one mechanism of viral clearance, and increases in some apoptotic markers were concurrent with the rise in serum ALT values, an indicator of hepatocyte damage. However, increases in apoptotic markers were present prior to a significant rise in serum ALT values and persisted beyond viral clearance. Since biochemical data do not always correlate with histological data, other mechanisms of cell death are likely involved during HCV infection.
Genes associated with HCV infection. Changes were observed in expression levels of several genes with specific relevance to HCV infection, including adipophilin, HCV microtubule aggregate protein, and Mac-2BP (31, 34, 52). Adipophilin associates with lipid droplets, is increased in pathological conditions such as alcoholic liver cirrhosis, and has been implicated as a marker for steatosis (31). The involvement of adipophilin in the generation of steatosis, a hallmark of HCV infection (48), requires further characterization. An increase in the HCV-associated microtubule aggregate protein was an anticipated outcome of HCV infection (34) and served as a positive internal control during the study. Both adipophilin and HCV-associated microtubule aggregate protein mRNA levels returned to baseline levels following viral clearance.
Mac-2BP is one of the 14 genes with an FC of >20 (Table 1; Fig. 2). Mac-2BP mRNA levels were 30-fold higher at day 7, steadily increased through week 6 (FC of >50), and returned to baseline levels by week 14. Increased levels of Mac-2BP have been demonstrated in hepatocellular carcinoma and HCV-infected patients and may be a marker for IFN- unresponsiveness in HCV chronically infected patients
(4, 18). The role of Mac-2BP in HCV infection is unclear,
although elevated levels of Mac-2BP mRNA did not correlate with the
development of chronicity, as the animal in this study cleared the infection.
Classical IFN-induced antiviral response. Three classical IFN response pathways (PKR, Mx proteins, and OAS) are generally associated with antiviral activity (54). Gale et al. and Taylor et al. demonstrated that HCV-encoded NS5A and E2, respectively, bind to and inhibit PKR function and proposed that modulation of PKR activity may be one mechanism by which the virus escapes the IFN response (27, 56). Therefore, the lack of an increase in PKR mRNA by microarray analysis, in the context of increases in the other two IFN response pathways (Fig. 2, MxA and OAS), was particularly notable. We sought to confirm these data using quantitative, real-time (TaqMan) RT-PCR. By TaqMan analysis, PKR mRNA increased fivefold by week 1, remained elevated through week 6, and returned to baseline levels by week 8 (data not shown). This finding was confirmed using serial liver samples from several other chimpanzees during the acute phase of infection. TaqMan analysis confirmed the microarray expression data for two other genes, adipophilin and IRF-1. The explanation for the disparity with PKR may lie in the choice of probes used in TaqMan versus microarray analysis. The TaqMan probe and primers for PKR mapped within the coding sequence of the gene, whereas all of the probe sets for PKR used in microarray analysis are encoded in the 3' untranslated region of the gene. Given that chimpanzee and human DNAs are highly homologous, sequence discrepancies are probably more likely in noncoding regions. Ultimately, virus replication in this animal was significantly curtailed despite possible NS5A/E2 modulation of PKR and presumably without a large specific immune cell infiltrate.
Resolution of infection.
Inherent to interpretation of the
data from this experiment is the observation that the chimpanzee
cleared viremia by week 8 and that peak serum ALT levels did not
coincide with the decline in viral RNA levels in the serum or liver.
These results suggest that viral clearance was not associated with
extensive hepatocellular death. This is consistent with our
observations that some animals clear viral infection without a
significant rise in serum ALT values (6, 36). Noncytolytic
mechanisms of viral RNA clearance have been demonstrated for hepatitis
B virus; in this case, however, the clearance is associated with
elevations in expression of IFN- and TNF- and a measurable
increase in T-cell markers in the liver (16, 30).
and TNF- mRNA levels in the liver remained
essentially unchanged by microarray analysis, although small increases
in mRNA levels were detected by TaqMan assay at week 6 (twofold for
IFN- and fourfold for TNF-). The significance of these changes is
questionable, since a twofold variation was observed between two
baseline samples taken 1 week apart prior to inoculation. Even if the
elevations in IFN- and TNF- that were observed by TaqMan at week
6 were accurate, the biological significance of such small increases is
not known.
Viral clearance must also be interpreted in context of the percentage
of hepatocytes infected. Peak viral RNA levels in the liver approached
1 ge per hepatocyte (105 ge/µg of liver RNA) (Fig. 1). If
the average infected cell contains at least 10 ge (1 to 2 copies of
negative strand RNA and 9 to 10 copies of positive-strand RNA), then no
more than 10% of hepatocytes were infected. The factors that limited
infection to a subset of hepatocytes may be the same factors involved
in viral clearance. Hepatocytes may respond to IFN- and subsequently
other cytokines by creating an environment incompatible with viral
replication. Such a scenario would rapidly proceed to a situation in
which limited available replication space existed within the liver as an increasing percentage of the uninfected hepatocytes became exposed
to IFN-. The spread of the infection would be limited, and a
decrease in viremia would ensue. However, it is unlikely that this
mechanism alone would result in complete viral clearance in the absence
of an adaptive immune response.
This hypothesis would explain the loss of viremia at 8 weeks p.i.,
prior to the elimination of viral RNA from the liver. Many IFN response
proteins were up-regulated, some of which have known antiviral effects
(e.g., OAS, PKR, Mx proteins, and STAT1 as an IFN response
transcriptional activator) and are probably important in controlling
virus spread and replication. The final phase of viral clearance may be
mechanistically different and may involve localized cytotoxic
T-lymphocyte-dependent or cytokine-mediated killing of the residual
infected cells. Detection of small increases in HCV-specific
CD4+ and CD8+ T cells above the resident
population of T cells in the liver may not be possible by microarray
analysis, since the liver is involved in the clearance of activated T
cells from the circulation (19). However, an early
cytotoxic T-lymphocyte response to multiple HCV antigens has been
associated with viral clearance in HCV-infected chimpanzees
(17). The data in this report do not minimize the role of
HCV-specific T cells in viral clearance. However, the data do
demonstrate that an early and extensive increase in IFN response genes
is associated with the clearance of viremia during acute infection.
Several lines of evidence support the importance of IFN-/ in
viral clearance. More recent therapies using pegylated IFN-2b with
ribavirin provide a high level of sustained viral clearance (29), suggesting that the low response rate of earlier
therapies was, in part, due to the inability to maintain IFN levels.
HCV infection may also result in down-regulation of the IFN response over time, making chronic infections particularly difficult to treat.
Indeed, the use of traditional IFN- monotherapy resulted in
virtually 100% viral clearance rate when applied to individuals during
the acute phase of infection (E. Jaekel, M. Cornberg, J. Mayer, J. N. Koerbel, H. Wedemeyer, A. Schueler, M. Zankel, C. Trautwein, and
M. P. Manns, Abstr. 51st Annu. Meet. Am. Assoc. Study Liver Dis.
abstr. 634, 2000). Other studies have demonstrated that the IFN-/
receptor is down-regulated in HCV chronically infected patients
(25, 26, 46). The importance of the host in IFN
responsiveness was also demonstrated when the virus from an
IFN-unresponsive patient became responsive to IFN when transmitted to
another individual (58). Finally, the sensitivity of HCV replication to IFN has been demonstrated in vitro using HCV replicons (10, 42).
The association of a vigorous IFN-/ response with clearance of
viremia in conjunction with the apparent biphasic pattern of viral
clearance observed in this chimpanzee suggests that both the innate and
adaptive immune responses play critical roles in elimination of HCV
during the acute phase of infection. This biphasic mechanism of viral
clearance is supported by the kinetics of viral decline observed during
IFN treatment of HCV infection. The early, rapid phase of viral decline
is hypothesized to involve inhibition of viral replication, while the
second, slower phase of decline is thought to result from the
destruction of infected hepatocytes (32, 38). Clearly, the
use of DNA microarray technology to examine the changes in gene
expression during the acute phase infection of HCV has provided new
insight into the role of IFN in viral clearance and many opportunities
for future studies on the myriad other changes observed.
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ACKNOWLEDGMENTS |
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We thank Bernadette Guerra for TaqMan analyses.
This work was supported by grants U19 AI40035 and P51 RR13986 from the National Institutes of Health.
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FOOTNOTES |
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* Corresponding author. Mailing address: 7620 NW Loop 410, San Antonio, TX 78227. Phone: (210) 258-9445. Fax: (210) 670-3329. E-mail: rlanford{at}icarus.sfbr.org.
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Abstract
Introduction
Materials and Methods
Results and Discussion
References
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Journal of Virology, August 2001, p. 7059-7066, Vol. 75, No. 15
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.15.7059-7066.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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