Hepatitis B virus (HBV) chronic infection is a critical risk factor for hepatocellular carcinoma. The innate immune response to HBV infection is a matter of debate. In particular, viral escape mechanisms are poorly understood. Our study reveals that HBV RNAs are not immunostimulatory in immunocompetent myeloid cells. In contrast, HBV DNA from viral particles and DNA replication intermediates are immunostimulatory and sensed by cyclic GMP-AMP Synthase (cGAS) and Stimulator of Interferon Genes (STING). We show that primary human hepatocytes express DNA sensors to reduced levels compared to myeloid cells. Nevertheless, hepatocytes can respond to HBV relaxed-circular DNA (rcDNA), when transfected in sufficient amounts, but not to HBV infection. Finally, our data suggest that HBV infection does not actively inhibit the DNA-sensing pathway. In conclusion, in infected hepatocytes, HBV passively evades recognition by cellular sensors of nucleic acids by (i) producing non-immunostimulatory RNAs, (ii) avoiding sensing of its DNAs by cGAS/STING without active inhibition of the pathway.
37HBV chronic infection is a critical risk factor for hepatocellular carcinoma. Although 38 debated, the absence of innate immune response to HBV infection in hepatocytes is becoming 39 the current view. However the underlying reasons are poorly understood. This study aims to 40 define potential viral pathogen-associated molecular patterns (PAMPs) and the pattern 41 Inducible Gene I (RIG-I) and Melanoma Differentiation-Associated protein 5 (MDA5) sense 81 foreign RNAs and activate Mitochondrial Antiviral Signaling Protein (MAVS), while foreign 82 viral DNA is recognized by sensors like cyclic GMP-AMP Synthase (cGAS). Activated cGAS 83 produces 2'3'-cyclic GMP-AMP (cGAMP), which activates Stimulator of Interferon Genes 84 (STING). STING or MAVS activation can both lead to the activation of Interferon Regulatory 85 Factor 3 (IRF3), which promotes IFN genes transcription [1]. To evade antiviral innate 86 responses, viruses have evolved escape strategies involving the inhibition of innate signaling 87 pathways by viral proteins, or the shielding of the viral genome from innate sensors (reviewed 88 in [1,2]). 89To date, more than 250 million people are chronically infected with HBV which is a 90 high-risk factor for liver cirrhosis and hepatocellular carcinoma. Its interplay with the 91 signaling pathways leading to IFN production is still a matter of debate. Some publications 92 described a type I and III IFN or pro-inflammatory response to HBV infection in cultured 93 hepatocytes [3][4][5][6]. HBV may also induce pro-inflammatory cytokines in immune cells such as 94 Kupffer cells, the liver macrophages, even if they are not productively infected [7][8][9]. The 95 induction of an innate response to HBV in infected hepatocytes has however been questioned 96 by several recent reports [8,[10][11][12][13], confirming initial studies in chimpanzees [14] and 97 patients [15,16]. Therefore, HBV was proposed to be a stealth virus in infected hepatocytes, 98 and the mechanisms behind the lack of innate responses are not fully understood. 99HBV particles contain a partially double-stranded DNA, the relaxed-circular DNA 100 (rcDNA), which is repaired into a covalently closed circular DNA (cccDNA) in the nuclei of 101 infected cells. The cccDNA is then transcribed into mRNAs and pregenomic RNA (pgRNA) 102 that are exported to the cytoplasm. The pgRNA is encapsidated into newly synthesized 103 capsids, where it is reverse transcribed into rcDNA. Both HBV RNAs and DNAs are 104 therefore potential PAMPs. HBV pgRNA has been proposed to be sensed by the RIG-I-[4] or 105 5 MDA5-pathways [3]. Surprisingly, MDA5 was also reported to bind HBV DNA [3]. 106 Recently, sensing of HBV DNA by the cGAS/STING pathway was suggested [17,10] but the 107 expression and functionality of this pathway in hepatocytes is unclear [8,10,13,17,18]. 108 Therefore, the immunostimulatory potential of HBV nucleic acids and the PRR involved 109 require further investigations. 110HBV could inhibit the innate immune response to escape its antiviral effec...
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