Hepatic stellate cells, liver innate immunity, and hepatitis C virus

Hepatic stellate cells, liver innate immunity, and hepatitis C virus

Several enveloped viruses including human immunodeficiency virus type 1 (HIV-1), cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), Ebola virus, vaccinia virus, and influenza virus have been found to incorporate host regulators of complement activation (RCA) into their viral envelopes and, as a result, escape antibody-dependent complement-mediated lysis (ADCML). Chronic hepatitis C virus (HCV) infection is thought to be associated with a higher prevalence of atherosclerotic vascular changes in the coronary artery, cerebrovascular artery, and carotid artery; however, little is known about the precise mechanisms by which HCV enhances atherogenic processes. DCs obtained ex vivo in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4 were loaded with HSV-1 proteins (DC/HSV-1 vaccine). Recent research in HCV genetics and molecular biology have led to significant advances in our understanding of the life cycle of this important pathogen and may ultimately lead to better antiviral strategies. Core needle biopsy evaluation is used to establish the diagnosis of recurrent HCV, which can be difficult to distinguish from acute cellular rejection and other causes of allograft dysfunction. Taken together, these results show that CCCM HCV transfer constitutes an important and effective route for HCV infection and dissemination. Hydroxyurea decreased induction in the first few hours after infection of A1–2 cells with irradiated HSV, suggesting that the biological events involving DNA synthesis which are required for induction by u.v.-HSV occur shortly after infection.

The risk is also increased if there are genital sores or ulcers from a sexually transmitted infection, or if either person also has HIV. These new observations highlight the importance of HSCs in liver immunity against HCV, which is the focus of this review paper. MMWR 1998;47[No. In summary, this study describes a direct interaction between HCV NS5A protein and cellular HK2 which is accompanied by an increase in HK2 activity that might contribute to an increased glycolysis rate during HCV infection. It is known that hepatic stellate cells (HSCs) are involved in HCV-induced liver fibrosis. The approximately 9.6-kb HCV genome contains a single open reading frame flanked by untranslated regions (UTRs) at its 5′ and 3′ ends (Figure 1).3 The internal ribosome entry site (IRES) located in the 5′-UTR directs cap-independent translation, whereas the 3′-UTR contains sequences critical for viral replication and translation.40 The 3′-UTR (positioned at nucleotides 9389–9679 of the HCV genome) contains a poly(U/UC) (PU/UC) tract located at nucleotide positions 9436–9600, which was identified as an HCV pathogen-associated molecular pattern (PAMP) that triggers RLR-mediated type I IFN production (Figure 1).22 Translation of the HCV genomic RNA produces a single polyprotein of approximately 3000 amino acids, which is further processed by cellular and viral proteases to yield the structural proteins core, E1 and E2 and the non-structural (NS) proteins p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B (Figure 1).3 NS proteins participate in different phases of the viral replication cycle (Figure 1). In this paper, we review the recent development in HSC-mediated immunity and the significance of these new observations.
Hepatic stellate cells, liver innate immunity, and hepatitis C virus

HCV represents one of the major causes of liver fibrosis. Liao et al compared the incidence of stroke between 4094 adults who were newly diagnosed with hepatitis C infection and 16,376 age- and sex-matched adults randomly selected from the database.28 They reported that the cumulative risk of stroke was significantly greater for people with hepatitis C than for those without infection (2.5% vs. HCV-infected hepatocytes release transforming growth factor-β1 (TGF-β1) and other profibrogenic factors that differentially modulate HSC expression of several key genes involved in liver fibrosis.17 HCV infection-induced hepatocyte apoptosis is a common feature in chronic HCV infection.18,19 Apoptosis results in the generation of apoptotic bodies (ABs), which are subsequently cleared by phagocytosis. Development of appropriate assays and model systems in Hepatitis C virus (HCV) research has been critical to the initial discovery of the etiological agent as well as having been integral to the discovery and development of antiviral therapies over the years that followed. The potential interaction between HSCs and HCV is suggested by the observation that HSCs express high levels of CD81 protein,23 a key entry coreceptor for HCV.24 It has been demonstrated that the HCV E2 protein can directly bind to CD81 on HSC surface, inducing fibrogenic effects on HSCs.25 In addition to HCV envelope protein, HCV core and nonstructural proteins have also been shown to affect HSC functions.26 Recombinant HCV core and NS3 proteins could increase intracellular calcium concentration and reactive oxygen species production in activated HSCs.26 HCV core protein could increase HSC proliferation, and NS3-NS5 protein preferentially induced pro-inflammatory cytokines in HSCs. Frequent alterations of HCV epitopes have been proposed to contribute to viral escape from recognition and elimination by the immune system (16, 17), yet it is highly conceivable that other mechanisms for evading the immune system are involved. HSCs have recently been implicated to play a novel role in the liver immunity.

It was reported that HSCs could induce vigorous natural killer T (NKT) cell responses in vitro and in vivo, and promote homeostatic proliferation of NKT cells.13 In addition, HSCs could elicit antigen-specific T cells and inhibit bacterial infection in a Listeria monocytogenes infection model.13 A recently study suggested that HSCs act as regulatory bystanders, enhancing differentiation and accumulation of regulatory T cells (Tregs), which may lie at the basis of the tolerogenic nature of the liver.9 HSCs could function as antigen presenting cells, as they have the ability to process protein antigens and present peptides to CD4+ and CD8+ T cells.13 Moreover, HSCs have been shown to express retinoic acid early inducible-1 (RAE1), cluster of differentiation 1d (CD1d), and major histocompatibility complex (MHC) I and II, and directly interact with immune cells, such as T cells,13 NKT cells,14 natural killer (NK) cells10 (). HSCs also express several pattern recognition receptors, such as Toll-like receptors (TLRs)12,30,31 and retinoic acid-inducible gene I (RIG-I),8 indicating that HSCs possess innate immunity against pathogen infection. These recommendations were made on the basis of a known epidemiologic association between a risk factor and acquiring HCV infection. RIG-I can detect viral genomic RNA during negative-strand RNA virus infection42 and trigger a type I IFN-mediated immune response that protects the host against viral infection.43 RIG-I can recognize HCV genome, inducing innate immune response to restrict HCV replication in hepatocytes.44 However, we know little about whether HSCs possess functional RIG-I signaling pathway and produce anti-HCV factors. Our recent studies examined whether HSCs have the ability to mount a RIG-I-mediated innate immunity that is effective in the control of HCV infection of human hepatocytes.8 We demonstrated that HSCs (LX-2 cells) possess functional RIG-I that can be activated by the RIG-I ligand, resulting in the induction of IFNs and inhibition of HCV replication in hepatocytes.8 This RIG-I signaling-mediated anti-HCV activity was potent, as when HCV JFH-1-infected hepatocytes were co-cultured with RIG-I-activated LX-2 cells or incubated in media conditioned with supernatant (SN) from RIG-I-activated LX-2 cells, HCV replication in hepatocytes was significantly suppressed.8 Further investigation showed that RIG-I-activated LX-2 cells produced both type I IFN (IFN-β) and type III IFN (IFN-λ).8 The role of IFNs in RIG-I-mediated HCV inhibition was evidenced by the observation that antibodies to type I IFN receptor or type III IFN receptor could compromise LX-2-SN-mediated anti-HCV effect in Huh7 cells.8 The importance of RIG-I-activated IFN signaling pathway in LX-2 cell-mediated anti-HCV activity was further demonstrated in the experiments, showing that inhibition of RIG-I by specific siRNA could block the IFN induction by 5′ppp-dsRNA.8 These new observations provide additional evidence to support the notion that the activation of RIG-I signaling in HSCs can help with the control of HCV infection/replication in the liver. The LVP attaches to SRB1 and to CD81 and further interacts with the tight junction protein claudin-1 and with occludin. As shown in , recent studies5–15 by several groups have clearly shown that HSCs are involved in the regulation of liver immunity.

It was shown that HSCs could act as a regulatory bystander, enhancing differentiation and accumulation of Tregs.9 Activated HSCs can also induce NK cell activation, which results in suppression of liver fibrosis and HCV infection.5–7,11 Furthermore, TLR-3 or RIG-I-activated HSCs could produce both type I and type III IFNs that could inhibit HCV replication in hepatocytes.8,12,15 These novel observations, although require further ex vivo and in vivo studies to confirm, highlight the importance of HSCs in liver immunity against HCV infection.

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