How HCV Manages to Stick Around
Abstract & Commentary
Synopsis: Persistence of hepatitis C virus after acute infection is the result of the ability of the viral serine protease to interfere with the production of antiviral proteins, including type 1 interferons.
Source: Foy E, et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003. In press.
Foy and colleagues investigated the molecular basis for the ability of hepatitis C virus (HCV) infection to escape the immune response and persist. Specifically, they examined the role of the HCV NS3/4A serine protease in interfering with host defenses.
Through a series of experiments, they demonstrated that HCV NS3/4A serine protease blocked the phosphorylation of latent interferon regulatory factor-3 (IRF-3) to its active form by virus-activated kinase. This resulted in blockade of transcription of type 1 interferons (IFN) and other antiviral genes important in the control of HCV replication. Finally, this blockade was reversed by inhibition of NS3/4A serine protease activity by SCH6, a specific inhibitor of this enzyme.
Comment by Stan Deresinski, MD, FACP
Hepatitis C evolves into a chronic infection in approximately 85% of those infected, with progression to cirrhosis in 20-30%. The high rate of mutation of this RNA virus and its evolution of innumerable quasispecies capable of escape from the adaptive immune response appear to account for its ability to persist once a state of chronic infection has been achieved. An important question that lacked an answer, however, was how the virus escaped the immune system in the time immediately after acute infection when large numbers of quasispecies were not yet present. The data of Foy et al provide evidence of a potential mechanism for this early escape.
Phosphorylation of IRF-3 by viral directed kinase leads to its translocation from cytoplasm to nucleus, where it induces the transcription of a series of antiviral genes, among them being type 1 IFNs. The HCV product, NS3/4A, disrupts this process by blocking the accumulation of phosphorylated IRF-3, as well as its translocation to the nucleus. The consequence is severe impairment of the antiviral response and the ability of HCV, having subverted this response, to persist in the cell, replicate and, thus, mutate.
The HCV NS3/4A enzyme complex contains a variety of catalytic properties, including acting as a serine protease necessary for post-translational processing the viral polyprotein, making it critical for viral replication. This criticality has made NS3/4A a target for new drug development. SCH6, one of a class of novel inhibitors of the protease, is one of these drugs. This study demonstrates that inhibition of the viral serine protease by SCH6 not only interferes with viral replication, but it also interferes with the ability of this enzyme to trigger the production of antiviral proteins, including type 1 interferons.
In summary, HCV has evolved a specific "work-around," allowing it to replicate without stimulating the production of interferons and other antiviral proteins and, thus, allowing it to persist in the infected host. The efficacy of newly developed inhibitors of HCV protease appear to have the ability to not only block viral replication, but also to prevent this method of circumvention of the innate immune response.
Dr. Derenski is Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center.
Synopsis: Persistence of hepatitis C virus after acute infection is the result of the ability of the viral serine protease to interfere with the production of antiviral proteins, including type 1 interferons.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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