Hepatitis C Virus Infection Is Blocked by HMGB1 Released from Virus-Infected Cells

Abstract

High-mobility group box 1 (HMGB1), an abundant nuclear protein that triggers host immune responses, is an endogenous danger signal involved in the pathogenesis of various infectious agents. However, its role in hepatitis C virus (HCV) infection is not known. Here, we show that HMGB1 protein is translocated from the nucleus to cytoplasm and subsequently is released into the extracellular milieu by HCV infection. Secreted HMGB1 triggers antiviral responses and blocks HCV infection, a mechanism that may limit HCV propagation in HCV patients. Secreted HMGB1 also may have a role in liver cirrhosis, which is a common comorbidity in HCV patients. Further investigations into the roles of HMGB1 in the diseases caused by HCV infection will shed light on and potentially help prevent these serious and prevalent HCV-related diseases.Hepatitis C virus (HCV) is one of the major causative agents of hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) (17, 30). More than 170 million people are estimated to suffer from HCV infection worldwide (17). Chronic and persistent infection is a characteristic feature of HCV pathogenesis (30). During chronic infection, the production of virus particles is limited, and a restricted number of liver cells are infected. As a result, the viral dose in patients' blood generally is lower than that of other hepatitis-causing viruses, such as hepatitis B virus (HBV) (4). Moreover, a large portion of hepatocytes often remains uninfected by the virus even after long-term infection (28). These phenomena indicate the existence of balance between the HCV infection process and host mechanisms that protect against HCV infection. We speculate that innate and adaptive immunities contribute to the balance between infection and protection.High-mobility group box 1 (HMGB1) protein is a highly conserved nuclear protein that participates in DNA organization and the regulation of transcription. In addition to its nuclear function, HMGB1 plays an important role as a cytokine, mediating the responses to infection, injury, and inflammation (1, 2, 29, 42). HMGB1 is released passively from necrotic cells and is actively secreted from activated immune cells, such as macrophages, natural killer cells, and mature dendritic cells (2). The functionality of actively secreted HMGB1 is known to be modulated by posttranslational modifications, such as oxidation (2, 36). Extracellular HMGB1 can function by itself and/or in association with other molecules, including CpG DNA, lipopolysaccharide (LPS), and interleukin-1 (IL-1) (5). HMGB1 induces a variety of cellular responses that contribute to innate immunity, tissue repair, and cell migration through interactions with various receptors that activate multiple signal transduction responses. The Toll-like receptors (e.g., TLR2, TLR4, and TLR9) and the receptor for advanced glycation end products (RAGE) are known receptors for the cytokine functions of HMGB1 (2). TLR4, the major component of the LPS recognition receptor complex, engages in downstream signaling through My...

Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

“…HMGB1 is translocated from the nucleus to the cytoplasm and subsequently is released into the extracellular milieu by HCV or HBV infection (61)(62)(63). Extracellular HMGB1 during HCV infection can trigger the interferon antiviral response through a TLR4-dependent pathway (61,63). HMGB1 serum levels are significantly higher in patients with chronic HBV than in normal healthy people and are closely related to the stage of inflammation and fibrosis in the liver ( Figure 4A) (64).…”

“…Although multiple signaling networks are responsible for coordinating the inflammatory and immune response during virus hepatitis, HMGB1 is critical in initiating and mediating these effects. HMGB1 is translocated from the nucleus to the cytoplasm and subsequently is released into the extracellular milieu by HCV or HBV infection (61)(62)(63). Extracellular HMGB1 during HCV infection can trigger the interferon antiviral response through a TLR4-dependent pathway (61,63).…”

HMGB1 Promotes Hepatitis C Virus Replication by Interaction with Stem-Loop 4 in the Viral 5′ Untranslated Region

“…2C). One recent study demonstrated that HMGB1 released from virus-infected cells could block HCV infection (35). Therefore, we speculated that the ectopic expression of HMGB1 may increase the amount of extracellular HMGB1, which partially neutralized the effect of intracellular HMGB1 on HCV propagation.…”

“…Both RNA virus, including hepatitis C virus, dengue virus, and human immunodeficiency virus (HIV) (34)(35)(36)(37), and DNA virus, including herpes simplex virus 2 (48) infections result in the secretion of HMGB1. HMGB1 protein secreted in response to viral infections may contribute to the pathogenesis of these infections.…”

“…HMGB1 was shown to be released from cells infected with a range of viruses, including dengue virus, HCV, and human immunodeficiency virus (HIV) (34)(35)(36)(37). Although a recent study suggested that HMGB1 released from virus-infected cells could block HCV infection, the role of intracellular HMGB1 in HCV replication and/or translation is still unclear (35). Moreover, HMGB1 has been identified as an indicator of human liver injury (38), and HMGB1 levels in the sera of patients with chronic hepatitis and cirrhosis are significantly elevated (39).…”