| | HCV offensive mechanisms versus host’s defensive strategiesReceived 20 October 2009; accepted 21 October 2009. published online 04 December 2009. Abstract At each stage of the life cycle of the virus, hepatitis C virus (HCV) interferes with the cellular antiviral mechanisms of the host. Therefore, HCV infection represents a fencing match between the virus and the host cell. The host’s defense depends primarily on activation of the immune response, including activation of interferon (IFN) signalling, expression of cytokines (TNF-α, IL-12, IL-10, IFN-α) and stimulation of cellular immune response (CIR) and humoral immune response (HIR). HCV offense relies on envelope mutation, evasion of the host immune response and interference with the endogenous cellular antiviral factors. Introduction  Worldwide, over 130 million people are estimated to be chronically infected with hepatitis C virus (HCV). Approximately 75% of HCV infected individuals develop chronic infections, which may in turn lead to cirrhosis, ESLD and HCC. Egypt has the highest HCV prevalence in the world. The prevalence of HCV in the country is 12% among the general population, reaching as high as 40% in persons above 40 years of age and in more in rural areas [1], [2]. Current interferon (IFN)-based therapies, such as 48week ribavirin treatment, achieve a sustained virologic response (SVR) in nearly 55% of patients [3], yet the remainder either show no response or experience a relapse when therapy is stopped [4], with a wide profile of side effects. The mechanisms underlying the failure of interferon therapy are not well understood, but evidence indicates that in addition to viral factors, several host factors are also involved [5]. Therefore, a novel approach for the treatment of HCV infection is needed for CHC patients. At each stage of the life cycle of the virus, HCV interferes with the cellular antiviral mechanisms of the host. The ability of the virus to persist within a host is attributed to its efficient ability to evade the adaptive and innate components of the host’s immune system. At present, the outcome of the conflict between host defence mechanisms and HCV counter measures favours the virus. A better understanding of the mechanisms leading to the initiation of infection is essential for the development of new therapeutic approaches targeting the early stage of the HCV replication cycle. Therefore, an approach targeting the host factors that are indispensable for the propagation of viruses might be an ideal target for the development of antiviral agents [6]. The life cycle of HCV The HCV life cycle begins with viral fusion with the receptor. Entry is followed by uncoating and viral translation, followed by viral replication through a negative-strand intermediate. The positive and negative RNA forms dsRNA, which is copied multiple times to generate the RNA genome. Finally, viral assembly, maturation and release occurs through Golgi and the cell membrane by a host secretory pathway. Viral cell entry After infection, HCV circulates in the bloodstream in different forms: free, or in a complex with immunoglobulin or lipoprotein (this represents 8–95% of the total plasma HCV RNA [7], [8]). The mechanisms through which this virus enters the cell are unknown, though CD81 [9] and scavenger receptor class-B type-1 [10] seem to be the key receptor components that mediate viral entry. In general, virus binding and internalisation are initiated by interaction between HCV-associated lipoproteins (VLDL) with lipoprotein receptors SR-B1 and/or LDL-R. After attachment to several cell surface molecules, HCV is directed to tight junctions where it interacts with CLDN1 and occludin, which may directly facilitate its cellular uptake. Similar to other flaviviruses, HCV entry is thought to be mediated by clathrin-mediated endocytosis, with delivery of the viral nucleocapsid via (early) endosomes. Hepatitis C viral receptors will be discussed in the following section. Tetraspanin CD81 receptors CD81 is an unglycosylated membrane protein. It is an integral member of the tetraspanin family that is ubiquitously expressed. A part of the B/T-cell receptor complex, the protein is involved in the fusion of vesicles [11], [12]. It also plays multiple roles in the processing, intracellular trafficking and membrane functions of CD19 [13]. It is expressed on cell surface, binds to E2 and mediates viral entry. Entry is reduced in the presence of antibodies to CD81 [9], in the presence of RNA interference (RNAi) which downregulates CD81, or in the presence of small molecules that bind to the host protein and prevent interaction with the receptor, eventually reducing viral entry. Scavenger receptor class-B type-1 (SR-B1) SR-B1 is a lipoprotein receptor that expresses and facilitates HCV entry [14]. It plays multiple roles in the processing, intracellular trafficking and membrane functions of CD19 [13]. However, this receptor is downregulated by IFN and RNAi to prevent viral entry. SR-B1 is expressed in various mammalian cells but is mostly expressed in the liver. It is a 509aa glycoprotein with two cytoplasmic domains, two transmembrane domains and a large extracellular loop with nine potential N-glycosylation sites [15], [16], [17]. SR-B1 is a ‘multi-ligand’ receptor for various classes of lipoproteins [high-, low- and very-low-density lipoproteins (HDL, LDL and VLDL, respectively)], as well as for chemically modified lipoproteins such as oxidised and acetylated LDL. A unique aspect of HCV compared with other viruses is that it has not been observed in its entire viral life cycle, associated with cholesterol metabolism in host cells. Thus, drugs that target cholesterol metabolism (statins) might be useful for treating HCV infection [18]. Further, drugs targeting the host proteins required for HCV infection, nuclear receptor or anti-receptor antibodies may be more helpful in combating the viral infection [19]. Low density lipoprotein receptor (LDL-R) Several reports have suggested that lipoproteins may play an important role in virus cell entry and initiation of infection. LDL-receptors have been implicated in HCV attachment, entry, and initiation of infection. Usually, HCV is associated with host lipoproteins (LDL, intermediate-density lipoprotein and VLDL) that facilitate virus uptake by low density lipoprotein receptors (LDL-R). A unique feature of HCV is the dependence of viral replication and assembly on host cell lipid metabolism. Consequently, lipoproteins and lipoprotein receptors play an essential role in viral uptake and initiation of infection. HCV cell entry is inhibited by natural ligands of lipoprotein receptors, such as VLDL and LDL, and by SAA enhanced by HDL and regulated by lipoprotein lipase (LPL). Role of lipoproteins in virus cell entry The liver plays a key role in the metabolism of plasma apolipoproteins, endogenous lipids and lipoproteins. A unique feature of HCV is that both RNA replication and virion assembly depend on cholesterol metabolism and fatty acid biosynthetic pathways in host cells [20], [21], [22], [23]. HCV infection is also known to induce large changes in cellular lipid metabolism, including abnormal (reduced) levels of serum lipoproteins and an accumulation of lipids in liver parenchymal cells (steatosis) [24], [25]. In general, HCV is transmitted via two primary routes: cell-free and cell-to-cell. Cell-free transmission begins when the virus is released from an infected cell and enters the extracellular environment. The virion can bind to surface-expressed receptors on naïve or uninfected cells, become internalised, and initiate new rounds of infection. En route from one cell to the next, the virus may encounter neutralising antibodies or other components of the immune response that may limit infection [6]. Pathogen-recognition receptors (TLR-3, RIG-1) Pathogen-recognition receptors (TLR-3, RIG-1) recognise the virus and trigger IFN release that blocks viral entry through downregulation of the receptor. The latter is antagonised by NS3/4 protease. Co-expression of only CD81 and SR-B1 is insufficient for viral entry. However, other potential receptors play a role in the entry of HCV; these include LDL receptor [26], negatively charged glycosaminoglycans, and (as Evans et al. [14] have recently suggested) the tight junction protein claudin-1 (CLDN1). Tight junction proteins: Claudin-1 (CLDN1) and occludin Tight junctions are major components of cell–cell adhesion complexes, separating apical from basolateral membrane domains and maintaining cell polarity by forming an intramembrane; this permits diffusion of certain molecules and limits others [27]. Evans et al. [14] have recently identified CLDN1, a member of the claudin gene family, as a new protein involved in HCV entry. CLDN1 is expressed in all epithelial tissues but predominantly in the liver, forming networks at tight junctions [28]. The expression of CLDN1 confers susceptibility to HCV pseudoparticle (HCVpp) infection in non-hepatic cell lines such as 293T and SW13 [14]. Currently available data suggest that HCV cell entry is a multi-step process requiring a set of entry molecules. CD81, SR-B1/Cla1 and the tight junction proteins CLDN1 and occludin are essential (co-)receptors for HCV cell entry. Recent data support the model that HCV enters the cell from tight junctions, even if the exact sequence of events leading to infection still remains unclear. Several observations have suggested that lipoproteins play an important role in virus cell entry and initiation of infection. On the other hand, virus binding and internalisation are initiated by the interaction between HCV-associated lipoproteins (mainly VLDL) with lipoprotein receptors SR-B1 and/or LDL-R and/or GAGs. HCV cooperates with the SR-B1–CD81 complex and the virus is subsequently transferred by CD81 to tight junction proteins CLDN1 and occludin. The virus enters the cell from the tight junction via endocytosis, and fusion is mediated by envelope glycoproteins; this event permits the virus to escape the lipoprotein degradation pathway. Lipoprotein-mediated HCV cell entry is inhibited by natural ligands of lipoprotein receptors, such as VLDL, LDL and oxidised LDL. Apart from lipoproteins, other host molecules, such as lipoprotein lipase (LPL) [29] or EWI-2wint [30], may contribute to the hepatotropism of HCV. Indeed, lipoprotein lipase (LPL), which targets lipoproteins to the liver, may be involved in the early steps of HCV cell entry. The various forms of HCV circulating in patient sera could allow the virus to use different cell entry pathways and thus different modes of infection [31]. The cellular uptake of HCV particles not associated with lipoproteins is mediated by the direct interaction of envelope glycoproteins with co-receptors. HCV particles are bound, presumably in a consecutive manner, by a complex formed by SR-B1 and CD81. Virus associated to CD81 is subsequently transferred to tight junctions where it interacts with CLDN1 and occludin. HCV then enters the cell by endocytosis and fusion of the viral envelope, with the membrane of an early endosome, leading to the release of the viral nucleocapsid into the cytoplasm. However, envelope-mediated HCV entry can be indirectly enhanced by HDL due to its action on the cholesterol transfer function of SR-B1, and can be inhibited by oxidised LDL, one of the natural SR-B1 ligands. Mechanisms of HCV survival in the host Viral entry During cell entry, HCV counteracts the host defensive strategies by impairing the function of DCs: limiting their ability to stimulate a robust antigen specific immune response in CD4+ and CD8+ T-cells. Recognition of the pathogen by PRR at the cell surface is impaired by NS3/4 protease and the high mutation rate within E2 HVR1 (escape mutations) that facilitate viral entry. Meanwhile, NS4A/B inhibits expression of MHC-I, which attenuates CD8+ response. Further impairment of T-cell function through upregulation of PD-1 and increased IL-10 production will end in HCV immune invasion. Inhibition of viral cell entry is accomplished by reduced expression of SR-B1-R with IFN and RNAi reducing viral entry. RIG-1 is activated by binding with viral RNA, inducing release of IFN and downregulating the receptor reducing viral entry. Viral proteins are taken up by DCs, degraded and bound with MHC-I/II and then presented to the cell surface activating CD8+ and CD4+ cells. CD4+ cells in turn activate B-cells to recreate antibodies that inhibit viral binding to CD81, preventing viral entry and mediating antibody-dependant cellular cytotoxicity (ADCC). The activation of CD8+ causes the secretion of TNF-α and IFN-γ, which boost host immune response. Viral translation Viral offensive mechanisms commence after entry and uncoating, when the viral genome is translated to the host translation machinery (IRES) for viral protein synthesis. Translation into a large polyprotein of 3000aa is followed by processing into structural (S) and non-structural (NS) proteins that are critical for viral replication and assembly. Viral protein synthesis is initiated and maintained as a result of inhibition of PKR/eIf-2α by E1/NS5A and IRES. During RNA translation, the host develops host-mediated defences, manifested by dsRNA formation through the coupling of positive-strand and negative-strand intermediate. dsRNA plays a key role in the host defensive mechanisms, triggering activation of PKR, which results in phosphorylation of elf-2α and the consequent shutting-down of initiation and maintenance of protein synthesis. Activation of TLR-3 and RIG-1 induces release of IFN-α/β, while dsRNA activates RNaseL, inhibiting protein synthesis. In addition, micro-RNA inhibits translation of RNA into protein [32]. Viral replication HCV replicates within enclosed structures, protecting viral RNA from host-mediated defences such as dsRNA, RNAi, cytokines and host immune response. HCV suppresses DCs function, which subsequently impairs CD4+ and CD8+ activation and eventually attenuates the host’s immune response. In addition, NS5B protein serves as a viral RNA dependant RNA polymerase (RdRp), which synthesises and elongates negative-strand HCVRNA. At the same time, RdRp lacks a proofreading ability, yielding mutants that evade the host’s immune response. Disruption of IFN signalling occurs via the JAK/STAT pathway by NS5A protein/core. Inhibition of transport of MHC-I to the cell surface by NS4A/B protein attenuates cellular immune response. All the above series of events contribute to the viral offensive mechanisms (see Fig. 1, Fig. 2, Fig. 3). Following HCV infection, host defensive strategies mediated by DCs take the form of early and robust intrahepatic activation of CD4+ and CD8+ associated with release of IFN that will achieve effective control of acute infection. In the meantime, host trafficking machinery transports peptides bound to MHC-I/II to the cell surface. These peptides can be recognised by activated CD4+/CD8+ cells respectively. CD4+ cells in turn activate B-cells to secrete antibodies that neutralise circulating virus and mediate ADCC, while CD8+ secrete TNF-α and IFN-γ, leading to non-cytolytic inhibition of viral replication (Fig. 4). dsRNA mediates host defence mechanisms via activation of PKR, which shuts down the viral protein synthesis, and activation of RNaseL, which degrades RNA and interferes with viral replication. Upon recognition of the pathogen by PRR, IFN is released, blocking viral entry through downregulation of the receptor. In general, cellular immune response to HCV infection is targeted to (Th1) cytokines, which clear viral infection. Replication yields hepatitis C virus genome (Fig. 5), which is a positive single stranded RNA virus – 9600 nts, that encodes 2 NCRs at both ends of the genome. The 5′ NCR contains an IRES that initiates translation of a single polyprotein of 3000 amino acids. The polyprotein is cleaved into 10 proteins; structural (core, E1and E2) and non-structural (P7, NS2, NS3, NS4A, NS4B, NS5A, NS5B). Structural proteins are cleaved from viral particles with the help of P7 and NS2, whereas non-structural proteins NS3 to NS5B are involved in genome replication [33], [34], [35], [36] (Fig. 6, Fig. 7, Fig. 8). Viral assembly and release Recent studies have underlined the importance of VLDL in the assembly and secretion of infectious HCV particles, in accordance with the association of the majority of the circulating virus with ApoB- and ApoE-containing lipoproteins and their role in virus infectivity [31]. HCV impairs DCs function by inhibiting interferon release, and attenuates cell-mediated immune (CMI) response of CD4+ and CD8+ by inhibiting the presentation of MHC-I/II bound with antigen on the cell surface of DCs. This in turn attenuates the host’s cellular immune response. NS5A protein mediates trafficking of virion to endoplasmic reticulum through Golgi apparatus for release of the virus. Eventually, the secreted HCV-associated lipoproteins might protect the secreted virus from antibody-mediated clearance. Glycosylation of E1/E2 in the endoplasmic reticulum provides more protection for the genome from the host’s antiviral strategies. On the other hand, the host’s dendretic cells – the main producers of interferon – express MHC-I bound with antigen that activate CD8+, eventually mediating non-cytolytic inhibition of viral replication. Initiation of the transport of MHC-I to the surface of infected hepatocyte [37] leads to lysis of infected cells by class-I restricted CTL. In the meantime, dendretic cells express MHC-II bound with antigen on the cell surface upon recognition of the antigen by CD4+, activating B-cells to produce antibodies that neutralise circulating virus and antagonise its binding with CD81 receptors. Finally, micro-RNAs (miRNA) are small RNAs that block packing and assembly, suggesting a role for miRNAs as antiviral effectors. dsRNA signals a cascade of IFN-α/β, whereas DCs have an important role in the activation of cellular immune response. The host immune response against HCV infection Viruses are endocytosed by local presenting cells (APCs), which present antigen to CD4+ cells in the form of peptides bound to the class II molecules. Upon antigen recognition, CD4+ cells release cytokines that regulate the activity of B-cells and CD8+ cells. B-cells produce antibodies that can neutralise circulating virus and may also participate in antibody-dependant cellular cytotoxicity (ADCC). The infected hepatocyte processes and presents HCV antigens coupled with MHC-I on its cell surfaces. CD8+ cytolytic cells (CTLs) can recognise HCV peptides in the context of an NHC-I class I molecule and help control viral replication through the killing of infected hepatocytes, as well as by non-cytolytic, cytokine-mediated inhibition of viral replication (Fig. 4). HCV interferes with numerous host defence mechanisms. In this, HCV replication yields mutations that impair virus detection by the host’s antiviral response. HCV NS3/4A protease antagonises signalling pathways of TLR-3, RIG-1 (PRRs), thus inhibiting IFN release tending to upregulation of PKR, mediating viral entry. •NS5A and core disrupt IFN signalling via the JAK-STAT pathway. •E1 and NS5A inhibit PKR, blocking elf-a activation and thus initiating and maintaining viral protein synthesis. Viral persistence Mechanisms underlying viral persistence and liver damage in chronic HCV have not yet been fully clarified, but a complex interplay of virological and immunological factors are implicated. An immunogenetic resistance or susceptibility to CHC infection may be linked to the human MHC. The class-I restricted CTL response is assumed to play a pivotal role in viral clearance and disease pathogenesis during HCV infections. CTL-mediated lysis of virus-infected host cells may lead to clearance of the virus or, if incomplete, to viral persistence and eventually chronic tissue injury. MHC-II is crucial in antigen presentation to T-helper (Th) cells by DCs. Mutations within recognised HCV T-cell epitopes may allow HCV variations to escape immune recognition and contribute to persistence. During replication, HCV constantly mutates. This helps the virus to evade the host’s immune response. In addition, HCV can replicate efficiently in extrahepatic sites by which the virus eludes eradication. Furthermore, the weak and non-maintained multi-specific immune response of CD4+ and CD8+ T-cells and the very low levels of antibodies produced by B-cells during the first 6months of infection will contribute to chronicity of infection. Summary HCV survival in the host ✓Viral defensive mechanisms: Replication within enclosed structures provides protection from the host’s antiviral defences. Genetic diversity created by inaccurate replication yields mutants resistant to the cell’s antiviral strategies. Association of the virion with protective lipoproteins protects the virus from the host’s antiviral response. ✓Viral offensive mechanisms: Virally encoded proteins (VEP) disrupt the ability of the host cells to detect the virus and downregulate the ability of the host cells to respond to interferon. VEP also impair innate immune defence mechanisms and prevent development of an effective B-cell-mediated humoral response. Host’s antiviral strategies ✓Augmentation of the host immune response: HCV particles are taken up by APCs which degrade viral proteins into peptides which are presented to the cell surface bound to MHC-I/II. Upon recognition of antigen by CD4+/CD8+, a robust cellular and humoral immune response is achieved. ✓Inhibition of viral entry•IFN and RNAi downregulate SR-B1, reducing viral entry. •Viral entry is reduced in presence of Abs to CD81. ✓Inhibition of viral translation•PKR activates eIF-2a, blocking translation of RNA. •Micro-RNA inhibits translation of RNA. •dsRNA activates latent ribonuclease (RNaseL), which inhibits RNA translation. ✓Inhibition of replication•DCs are a major source of IFN, while PRR triggers signalling of interferon which interferes with replication. •dsRNA activates RNaseL, which degrades RNA while PKR shuts-down protein synthesis. ✓Disruption of packing and assembly•Micro-RNA and statins disrupt packing and assembly of the virion. In Conclusion, HCV infection represents a fencing game between the virus and the host cell. Host defence depends primarily on the host’s immune response and on activation of IFN signalling pathway (ISGs→2′5′ OAS – RNaseL, and PKR). PKR normally antagonises RNA translation by activated elf-α. On the other hand, dsRNA activates the JAK-STAT pathway and ISGs, inducing IFN production. In general, the host’s antiviral mechanisms rely primarily on antagonising RNA translation and inhibiting viral replication, while augmenting the host’s immune mechanisms. Meanwhile, HCV offence relies on envelope mutation and evasion of the host immune response in addition to interference with endogenous cellular antiviral factors. However, IFN production is inhibited by core protein through the induction of suppressor of cytokines (SOCs), which decrease the ability of DCs to produce IFN. Furthermore, IFN activity is attenuated by NS5A protein through activation of IRF1 and induction of IL-8. 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Tropical Medicine Department, Ain Shams University and Cairo Liver Center, Egypt  Tel.: +20 2 37603002; fax: +20 2 37481900.
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