Comparative Analysis of Anti-Hepatitis C Virus Activity and Gene Expression Mediated by Alpha, Beta, and Gamma Interferons

Abstract

A direct comparison of the inhibitory effects of alpha, beta, and gamma interferons (IFNs) on replication of a hepatitis C virus subgenomic replicon in a hepatoma cell line revealed similarities in antiviral potency. However, alternate IFN-induced antiviral mechanisms were suggested following observations of striking differences between IFN-␥ and IFN-␣/␤ with respect to strength and durability of the antiviral response and the magnitude and pattern of IFN-mediated gene expression.Interferons (IFNs) are a family of cytokines that share the property of inducing proteins that inhibit virus replication (23). IFNs are not constitutively synthesized by cells but respond to external stimuli, such as virus infections, that trigger their transient synthesis and secretion. Binding of IFN to its receptor elicits signals that induce the transcription of a specific set of genes. These genes encode proteins that carry out the diverse functions of the IFN system including mediating antiviral activity. IFNs are classified as either alpha/beta IFN (IFN-␣/␤) or IFN-␥. IFN-␣ and -␤ are readily induced by double-stranded viral RNA, primarily in leukocytes and fibroblasts. These IFNs then induce some of the known IFN-responsive antiviral effector mechanisms, including (i) 2Ј,5Јoligoadenylate synthetase (2Ј,5Ј-OAS) (which then activates the constitutively expressed RNase L to degrade viral RNAs), (ii) double-stranded RNAactivated protein kinase (which inhibits viral protein synthesis), and (iii) MxA (a GTPase that blocks transport of viral ribonucleoproteins to the nucleus) (23). The IFN-␣/␤-regulated genes induce direct antiviral activity as part of the early or innate host immune response to limit viral infection. The host adaptive antiviral response mediated by CD8 ϩ cytotoxic T lymphocytes and natural killer cells and by virus-specific neutralizing antibodies then eradicates virus and virus-infected cells. IFN-␥ is induced as part of the adaptive immune response by a wide variety of stimuli and is restricted to T cells and natural killer cells (4). Little is known about the direct antiviral activity of IFN-␥, particularly with respect to the mechanism, magnitude, and kinetics of its antiviral activity in comparison with IFN-␣ and -␤.Hepatitis C virus (HCV), a member of the Flaviviridae family, has a single-stranded positive-sense RNA genome encoding a polyprotein of at least 10 distinct gene products (5). Infections caused by HCV are a major medical concern since as much as 3% of the worldwide population is estimated to be HCV seropositive (1). At present, the most widely prescribed HCV antiviral therapy is the combination of polyethylene glycol-modified IFN-␣2b (PEG-Intron) and ribavirin (18), a treatment capable of inducing sustained virologic responses in 54 to 56% of chronically infected patients (11a, 18). Although this is a significant improvement from the sustained response rate of IFN-␣ monotherapy (6 to 16%) (7, 21, 24) and IFN-␣ plus ribavirin (40%) (8, 19), improvement in sustained response rates still remains the majo...

T cell–dependent production of IFN-γ by NK cells in response to influenza A virus

“…IFN-γ is known for its immune regulatory activity as well as direct antiviral activity (17)(18)(19)(20)(21)(22)(23)(24)(25). Rapid production of IFN-γ and other inflammatory cytokines by NK cells is an important component of the innate immune response against viral infections (12), which has been shown to be mediated by IL-12 in a murine CMV-infected mouse model (32,33).…”

“…By contrast, the CD56 bright subset has the capacity to produce abundant cytokines and may serve as immunoregulators (15,16). One of the cytokines produced by CD56 bright NK cells is IFN-γ, which has immune regulatory activity (17)(18)(19)(20)(21) as well as direct antiviral activity (22)(23)(24)(25).…”

Interference of hepatitis C virus RNA replication by short interfering RNAs

“…The recent development of subgenomic and full-length HCV replicons that replicate and express HCV proteins in stably transfected human hepatoma cell-derived Huh-7 cells has facilitated the analysis of the role of cellular pathways required in HCV replication and the efficacy of antiviral drugs (15)(16)(17)(18)(19). For example, by using HCV replicons, the antiviral effects of IFN␣ and IFN␥ have been clearly demonstrated (20)(21)(22)(23). Although IFN treatment can efficiently inhibit HCV replication in cultured Huh-7 cells, Ͼ60% of patients treated with IFN do not eliminate the virus (24)(25)(26)(27)(28).…”

Increased Protection from Vaccinia Virus Infection in Mice Genetically Prone to Lymphoproliferative Disorders

“…The FAS-670A/A polymorphism has also been associated with viral clearance in patients with HCV (30). IFN-␥ has been shown to directly inhibit HCV in virus replicon systems, and this mechanism could explain this association (9,14). Alternatively, decreased expression of Fas might also limit inflammation in the liver during HCV infection, as Fas expression has previously been correlated with inflammation in liver samples of patients with chronic HCV (15).…”