Chapter 2 - Adaptive Immunity to the Hepatitis C Virus
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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Cited by (63)
Early high levels of regulatory T cells and T helper 1 may predict the progression of recurrent hepatitis C after liver transplantation
2019, Clinics and Research in Hepatology and GastroenterologyCitation Excerpt :The mechanisms by which HCV evades the immune surveillance system remain unclear, and persistent infection appears to be due to weak CD4+ and CD8+ T cell responses during acute infection, which fail to control viral replication [5,6]. The impairment of T cell responses is multifactorial [7,8], including skewed T cell differentiation [T helper1 (Th1) deficiency, Th2 dominance] [9], the elevated secretion of inhibitory cytokines such as interleukin-10 (IL-10) and TGF-Ī² which create an immunosuppressive environment [10,11], an up regulation of inhibitory pathways [programmed death-1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4, CD152)] [12,13], impairment of the allostimulatory capacity of both myeloid and plasmacytoid dendritic cells [14], and the induction of regulatory T cells (Tregs) [15]. Attention has recently focused on Tregs and their contribution to HCV disease.
Dynamic changes in CD45RA<sup>-</sup>Foxp3<sup>high</sup> regulatory T-cells in chronic hepatitis C patients during antiviral therapy
2016, International Journal of Infectious DiseasesCitation Excerpt :The accumulation of Treg cells plays a pivotal role in suppressing the antiviral effector T-cells that are essential for viral clearance.5,6 Recently, a growing body of evidence has indicated that Treg cells may contribute critically to the induction of immune tolerance and affect the proliferation, differentiation, and cytokine secretion of HCV-specific lymphocytes.7ā11 Some research groups have reported that the depletion of Treg cells increases the frequency of autoimmune reactions and enhances the development of autoimmune disease.12ā15
The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control
2016, Journal of HepatologyCitation Excerpt :Yet it is equally clear that HCV can readily escape strong cellular immune responses [90,249]. An impressive array of studies have defined the components of cellular host responses involved with HCV infections [76,292], including groundbreaking CD4+ and CD8+ T cell depletion studies in chimpanzees that confirmed a critical role of these T cell responses in the control of HCV [293,294]. Thus, the goal of any T cell based vaccine is to induce responses with desirable phenotypes of immune cells.
Evolution of the Humoral Response during HCV Infection: Theories on the Origin of Broadly Neutralizing Antibodies and Implications for Vaccine Design
2016, Advances in ImmunologyCitation Excerpt :Importantly, the suppression of the innate immune response is likely detrimental to processes such as antigen processing and presentation which may potentiate the delayed emergence of the adaptive immune response (reviewed in Szabo & Dolganiuc, 2008). Upon reaching peak viral load at approximately 4 weeks postinfection, a distinct decline in the viral load is observed at 4ā8 weeks thereafter, which is concurrent with the emergence of the cytotoxic T lymphocyte (CTL) response (Cox et al., 2005; Neumann-Haefelin & Thimme, 2011; Park & Rehermann, 2014; Rehermann, 2009; Walker, 2010). Furthermore, the emergence of the cellular response also drives the appearance of the quasispecies due to the high viral replication rate of 1012 viral particles daily involving a low fidelity viral RNA polymerase (Neumann et al., 1998; Simmonds, 2004).
A prophylactic hepatitis C virus vaccine: A distant peak still worth climbing
2014, Journal of HepatologyCitation Excerpt :These attempts at vaccination might not be successful right away, but carefully planned human trials and the analysis of the clinical, virological and immunological features of vaccination and the dissection of the response to HCV exposure or infection will contribute essential information to improve vaccine strategies. Evidence from chimpanzee and human studies support critical roles for CD4 and CD8 T lymphocyte responses in the control of primary and secondary HCV infection [14ā28]. The strongest evidence comes from T cell depletion experiments in the chimpanzee model, where a lack of either CD4 or CD8 T cells during exposure and early infection was associated with persistent viraemia [18,26].
Signatures of protective memory immune responses during hepatitis C virus reinfection
2014, Gastroenterology