Chapter 2 - Adaptive Immunity to the Hepatitis C Virus

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Abstract

The hepatitis C virus (HCV) is a global public health problem affecting approximately 2% of the human population. The majority of HCV infections (more than 70%) result in life-long persistence of the virus that substantially increases the risk of serious liver diseases, including cirrhosis and hepatocellular carcinoma. The remainder (less than 30%) resolves spontaneously, often resulting in long-lived protection from persistence upon reexposure to the virus. To persist, the virus must replicate and this requires effective evasion of adaptive immune responses. In this review, the role of humoral and cellular immunity in preventing HCV persistence, and the mechanisms used by the virus to subvert protective host responses, are considered.

Introduction

The existence of hepatitis C virus(es) was first predicted 35 years ago to explain transfusion-associated liver disease in individuals not infected with the hepatitis A or B viruses (Alter et al., 1975, Feinstone et al., 1975, Prince et al., 1974). The description in 1989 of a single hepatitis C virus (HCV) that caused most posttransfusion and community acquired non-A non-B hepatitis marked a significant turning point toward understanding the epidemiology, natural history, and pathogenesis of this disease (Choo et al., 1989, Houghton, 2009). Seroepidemiology studies indicate that HCV has infected approximately 2% of the world's population. The virus establishes persistent, life-long viremia in about 75% of infected humans and significantly increases the risk of progressive liver diseases, including inflammation, cirrhosis, and hepatocellular carcinoma. The discovery of HCV has also facilitated the development of new small molecule inhibitors of virus replication (designated STAT-C agents) that will soon be an adjunct to, and perhaps eventually replace, current standard therapy with pegylated type I interferon and ribavirin that is toxic, expensive, and frequently ineffective (Shimakami et al., 2009).

HCV is a member of the Flaviviridae and the prototype virus in the hepacivirus genus (Moradpour et al., 2007). It has a small RNA genome of about 10,000 nucleotides encoding a single polyprotein of 3000 amino acids that is processed by host cell and viral proteases into 10 in-frame proteins (Moradpour et al., 2007). At least one small frame-shifted protein of unknown function is also produced. Structural proteins include a core or nucleocapsid and two envelope glycoproteins. Seven nonstructural proteins are important for HCV replication. There are at least six distinct genotypes that can be further classified into subtypes defined by phylogenetic relationships (Simmonds et al., 2005). HCV circulates as a population of different but closely related genomes in infected individuals (Simmonds et al., 2005). How the virus manages to avoid immune responses and establish life-long persistence is still a mystery. It is apparent that most viral proteins important for HCV replication also participate in evasion of innate and/or adaptive immune responses. As an example, the NS3 helicase/protease is critical for HCV replication and a prime target for small-molecule STAT-C inhibitors. NS3 protease activity also disrupts induction of innate immune defenses through RIG-I (retinoic acid inducible gene 1) and toll-like receptor 3 (TLR-3) sensors by cleavage of cellular intermediates important in signal transduction (Foy et al., 2003, Gale & Foy, 2005, Li et al., 2005). Despite the tremendous efficiency of HCV in establishing persistence, spontaneous clearance of infection in some individuals provides optimism that chronic hepatitis C can be prevented by vaccination and perhaps treated by immunotherapeutic approaches.

Section snippets

Patterns of HCV Replication

HCV replication and adaptive immune responses have been studied in humans and chimpanzees, the only species other than man with known susceptibility to infection. Transmission of non-A non-B hepatitis from humans to chimpanzees provided an animal model for initial characterization of the agent as a small enveloped RNA virus and paved the way for molecular cloning of the HCV genome (Alter et al., 1978, Hollinger et al., 1978, Tabor et al., 1978). Although there have been few detailed studies of

Humoral Immunity to HCV

It has been known for two decades that seroconversion is substantially delayed during acute hepatitis C, with serum antibodies appearing several weeks after the initiation of virus replication regardless of infection outcome (Chen et al., 1999). Progress toward understanding the role of antibodies in HCV infection has been slow. This is due almost entirely to the technically challenging task of studying HCV attachment and entry into host cells, and whether this process is susceptible to

Cellular Immunity to HCV

Several observations indicate a critical role for cell-mediated immunity in spontaneous resolution of HCV infection. To summarize, early studies of infection in humans and chimpanzees established a temporal kinetic relationship between initial control of acute phase viremia and expansion of functional CD4+ helper and CD8+ cytotoxic T cells (Bowen & Walker, 2005a, Rehermann, 2009). To prevent persistence, these responses must be sustained past the point that viral genomes are eradicated from

Immunity Acquired by Natural Infection Can Protect Against HCV Persistence: Implications for Vaccination

HCV-specific T cells are detectable in blood for at least two decades after resolution of infection even in humans who no longer have detectable antibody responses to the virus (Takaki et al., 2000). There is evidence that memory T cells primed naturally by successful resolution of infection protect against persistence upon reexposure to the virus. Studies involving humans serially exposed to the virus through intravenous drug use have provided valuable insight into this issue. Virus

Summary

HCV is somewhat unique amongst human viruses in its ability to establish either persistent life-long infection or durable immunity that can protect against persistence after reexposure to the virus. This has provided a unique opportunity to define mechanisms of protective immunity and evasion by a small human RNA virus. Mutational escape from humoral and cellular immune responses is a common finding in humans and chimpanzees with a persistent outcome of infection. However, this mechanism alone

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