Hepatitis B cured by the activation of intrahepatic innate immunity:Research advances and new strategies
-
摘要:
宿主天然免疫和适应性免疫应答对HBV的清除至关重要。慢性HBV感染者体内针对HBV的天然免疫和特异性免疫应答存在缺陷,不能有效清除病毒,导致病毒持续复制和肝脏炎症。除了直接抑制HBV,针对宿主免疫的治疗策略如刺激或重塑抗病毒免疫也是实现慢性乙型肝炎患者功能性治愈的重要手段之一。肝脏是HBV感染的靶器官,因此研究HBV感染对肝内免疫微环境的影响是当前调控肝内抗病毒免疫应答的新药研发热点。主要阐述了HBV感染相关天然免疫应答的研究进展和激活肝内天然免疫应答治愈乙型肝炎的新策略。
Abstract:Host innate and adaptive immune responses are essential for the clearance of hepatitis B virus(HBV). Patients with chronic HBV infection have defects in innate and specific immune responses against HBV, which cannot effectively eliminate the virus and may result in persistent virus replication and liver inflammation. In addition to direct inhibition of HBV, treatment strategies targeting host immunity,such as stimulating or restoring antiviral immunity, are also important methods to achieve functional cure in patients with chronic hepatitis B.The liver is the target organ for HBV infection, and therefore, the research on the impact of HBV infection on intrahepatic immune microenvironment has become a hotspot for the research and development of new drugs that regulate the antiviral immune response against HBV in the liver. This article reviews the recent research advances in innate immune response associated with HBV infection and the new strategies to activate intrahepatic innate immune response and achieve the cure of hepatitis B.
-
Key words:
- hepatitis B virus /
- hepatitis B,chronic /
- immunity,innate /
- immunotherapy
-
[1] LANCET T. Carving a new path to a hepatitis B cure[J]. Lancet, 2020, 394(10216):2202. [2] BERG T, SIMON KG, MAUSS S, et al. Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients-FINITE study[J]. J Hepatol,2017, 67(5):918-924. [3] AKIRA S, UEMATSU S, TAKEUCHI O. Pathogen recognition and innate immunity[J]. Cell, 2006, 124(4):783-801. [4] LESTER SN, LI K. Toll-like receptors in antiviral innate immunity[J]. J Mol Biol, 2014, 426(6):1246-1264. [5] DUNN C, PEPPA D, KHANNA P, et al. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection[J]. Gastroenterology, 2009, 137(4):1289-1300. [6] HUANG YW, LIN SC, WEI SC, et al. Reduced Toll-like receptor 3 expression in chronic hepatitis B patients and its restoration by interferon therapy[J]. Antivir Ther, 2013, 18(7):877-884. [7] VISVANATHAN K, SKINNER NA, THOMPSON AJ, et al. Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein[J]. Hepatology, 2007, 45(1):102-110. [8] XU N, YAO HP, LV GC, et al. Downregulation of TLR7/9leads to deficient production of IFN-αfrom plasmacytoid dendritic cells in chronic hepatitis B[J]. Inflamm Res, 2012,61(9):997-1004. [9] SATO S, LI K, KAMEYAMA T, et al. The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus[J]. Immunity, 2015, 42(1):123-132. [10] HE J, HAO R, LIU D, et al. Inhibition of hepatitis B virus replication by activation of the cGAS-STING pathway[J]. J Gen Virol, 2016, 97(12):3368-3378. [11] CUI X, CLARK DN, LIU K, et al. Viral DNA-dependent induction of innate immune response to hepatitis B virus in immortalized mouse hepatocytes[J]. J Virol, 2016, 90(1):486-496. [12] MONDELLI MU, OLIVIERO B, MELE D, et al. Natural killer cell functional dichotomy:A feature of chronic viral hepatitis?[J]. Front Immunol, 2012, 3:351. [13] GUY CS, MULROONEY-COUSINS PM, CHURCHILL ND, et al. Intrahepatic expression of genes affiliated with innate and adaptive immune responses immediately after invasion and during acute infection with woodchuck hepadnavirus[J]. J Virol, 2008, 82(17):8579-8591. [14] SUN C, FU B, GAO Y, et al. TGF-β1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence[J]. PLoS Pathog, 2012, 8(3):e1002594. [15] OKAZAKI A, HIRAGA N, IMAMURA M, et al. Severe necroinflammatory reaction caused by natural killer cell-mediated Fas/Fas ligand interaction and dendritic cells in human hepatocyte chimeric mouse[J]. Hepatology, 2012, 56(2):555-566. [16] ZHANG Z, ZHANG S, ZOU Z, et al. Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients[J]. Hepatology, 2011, 53(1):73-85. [17] ZHANG JY, ZOU ZS, HUANG A, et al. Hyper-activated pro-inflammatory CD16 monocytes correlate with the severity of liver injury and fibrosis in patients with chronic hepatitis B[J].PLoS One, 2011, 6(3):e17484. [18] BILITY MT, CHENG L, ZHANG Z, et al. Hepatitis B virus infection and immunopathogenesis in a humanized mouse model:Induction of human-specific liver fibrosis and M2-like macrophages[J]. PLoS Pathog, 2014, 10(3):e1004032. [19] HEYMANN F, PEUSQUENS J, LUDWIG-PORTUGALL I, et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells[J]. Hepatology, 2015, 62(1):279-291. [20] SITIA G, IANNACONE M, AIOLFI R, et al. Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis[J]. PLoS Pathog, 2011, 7(6):e1002061. [21] ZHU QR, CHEN F, YU XQ, et al. Advances in the study of dendritic cells in the pathogenesis of chronic hepatitis B[J]. J North Sichuan Med Coll, 2019, 34(6):828-831.(in Chinese)朱其荣,陈芳,喻雪琴,等.树突状细胞在慢性乙型肝炎发病机制中的研究进展[J].川北医学院学报,2019, 34(6):828-831. [22] GOLSAZ-SHIRAZI F, AMIRI MM, SHOKRI F. Immune function of plasmacytoid dendritic cells, natural killer cells, and their crosstalk in HBV infection[J]. Rev Med Virol, 2018, 28(6):e2007. [23] YONEJIMA A, MIZUKOSHI E, TAMAI T, et al. Characteristics of impaired dendritic cell function in patients with hepatitis B virus infection[J]. Hepatology, 2019, 70(1):25-39. [24] ZHANG X, MA Z, LIU H, et al. Role of Toll-like receptor 2 in the immune response against hepadnaviral infection[J]. J Hepatol, 2012, 57(3):522-528. [25] WU J, CHEN MF, XIA YC, et al. Toll-like receptor dependent innate immune responses by primary mouse hepatocytes and its control of HBV replication[J]. Chin J Hepatol, 2011,19(11):838-842.(in Chinese)吴珺,陈明发,夏幼辰,等.Toll样受体介导小鼠原代肝细胞产生的天然免疫应答及其对乙型肝炎病毒复制的抑制作用[J].中华肝脏病杂志,2011, 19(11):838-842. [26] SATO S, LI K, KAMEYAMA T, et al. The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus[J]. Immunity, 2015, 42(1):123-132. [27] FISICARO P, VALDATTA C, BONI C, et al. Early kinetics of innate and adaptive immune responses during hepatitis B virus infection[J]. Gut, 2009, 58(7):974-982. [28] MCNAB F, MAYER-BARBER K, SHER A, et al. Type I interferons in infectious disease[J]. Nat Rev Immunol, 2015, 15(2):87-103. [29] PURO R, SCHNEIDER RJ. Tumor necrosis factor activates a conserved innate antiviral response to hepatitis B virus that destabilizes nucleocapsids and reduces nuclear viral DNA[J]. J Virol, 2007, 81(14):7351-7362. [30] BIERMER M, PURO R, SCHNEIDER RJ. Tumor necrosis factor alpha inhibition of hepatitis B virus replication involves disruption of capsid Integrity through activation of NF-kappaB[J]. J Virol, 2003, 77(7):4033-4042. [31] XIA Y, STADLER D, LUCIFORA J, et al. Interferon-γand tumor necrosis factor-αproduced by T cells reduce the HBV persistence form, cccDNA, without cytolysis[J]. Gastroenterology, 2016, 150(1):194-205. [32] VALAYDON Z, PELLEGRINI M, THOMPSON A, et al. The role of tumour necrosis factor in hepatitis B infection:Jekyll and Hyde[J]. Clin Transl Immunology, 2016, 5(12):e115. [33] YU WH, COSGROVE C, BERGER CT, et al. ADCC-mediated CD56DIM NK cell responses are associated with early HBsAg clearance in acute HBV infection[J]. Pathog Immun,2018, 3(1):2-18. [34] STELMA F, de NIET A, TEMPELMANS PLAT-SINNIGE MJ,et al. Natural killer cell characteristics in patients with chronic hepatitis B virus(HBV)infection are associated with HBV surface antigen clearance after combination treatment with pegylated interferon alfa-2a and adefovir[J]. J Infect Dis, 2015,212(7):1042-1051. [35] BONI C, LAMPERTICO P, TALAMONA L, et al. Natural killer cell phenotype modulation and natural killer/T-cell interplay in nucleos(t)ide analogue-treated hepatitis e antigen-negative patients with chronic hepatitis B[J]. Hepatology, 2015,62(6):1697-1709. [36] YANG F, YU X, ZHOU C, et al. Hepatitis B e antigen induces the expansion of monocytic myeloid-derived suppressor cells to dampen T-cell function in chronic hepatitis B virus infection[J]. PLoS Pathog, 2019, 15(4):e1007690. [37] LÜTGEHETMANN M, BORNSCHEUER T, VOLZ T, et al. Hepatitis B virus limits response of human hepatocytes to interferon-αin chimeric mice[J]. Gastroenterology, 2011, 140(7):2074-2083,2083. e1-2. [38] JI C, SASTRY KS, TIEFENTHALER G, et al. Targeted delivery of interferon-αto hepatitis B virus-infected cells using Tcell receptor-like antibodies[J]. Hepatology, 2012, 56(6):2027-2038. [39] PHILLIPS S, MISTRY S, RIVA A, et al. Peg-interferon lambda treatment induces robust innate and adaptive immunity in chronic hepatitis B patients[J]. Front Immunol, 2017, 8:621. [40] ISOGAWA M, ROBEK MD, FURUICHI Y, et al. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo[J].J Virol, 2005, 79(11):7269-7272. [41] MENNE S, TUMAS DB, LIU KH, et al. Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620in the Woodchuck model of chronic hepatitis B[J]. J Hepatol,2015, 62(6):1237-1245. [42] HUANG LR, WOHLLEBER D, REISINGER F, et al. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+)T cells and successful immunotherapy against chronic viral liver infection[J]. Nat Immunol, 2013, 14(6):574-583. [43] NIU C, LI L, DAFFIS S, et al. Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism[J]. J Hepatol, 2018, 68(5):922-931. [44] LANFORD RE, GUERRA B, CHAVEZ D, et al. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees[J]. Gastroenterology, 2013, 144(7):1508-1517,1517. e1-10. [45] AGARWAL K, AHN SH, ELKHASHAB M, et al. Safety and efficacy of vesatolimod(GS-9620)in patients with chronic hepatitis B who are not currently on antiviral treatment[J]. J Viral Hepat, 2018, 25(11):1331-1340. [46] HERSCHKE F, LI C, CREUS AD, et al. PS-076-Antiviral activity of JNJ-4964(AL-034/TQ-A3334), a selective tol-like receptor 7 agonist, in AAV/HBV mice after oral administration for 12weeks[J]. J Hepatol, 2019, 2019:e49-e50. [47] DAI L, YU Y, GU L, et al. Combination treatment of a TLR7agonist RO7020531and a capsid assembly modulator RO7049389 achieved sustainable viral loadsuppression and HBsAg loss in an AAV-HBV mouse model[J]. J Hepatol,2018, 68:s17-s18. [48] JO J, TAN AT, USSHER JE, et al. Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver[J]. PLoS Pathog, 2014, 10(6):e1004210. [49] DAFFIS S, CHAMBERLAIN J, ZHENG J, et al. SAT-165-Sustained efficacy and surface antigen seroconversion in the woodchuck model of chronic hepatitis B with the selective toll-like receptor 8 agonist GS-9688[J]. J Hepatol, 2017, 66(1 Suppl):s692-s693. [50] AMIN OE, COLBECK E, DAFFIS S, et al. In vitro modulation by TLR8 agonist GS-9688 of multiple regulatory cell types in patients with chronic hepatitis B[J]. J Hepatol, 2019, 70:e445. [51] MENG Z, ZHANG X, PEI R, et al. Combination therapy including CpG oligodeoxynucleotides and entecavir induces early viral response and enhanced inhibition of viral replication in a woodchuck model of chronic hepadnaviral infection[J]. Antiviral Res, 2016, 125:14-24. [52] PAULSEN D, KOROLOWICZ KE, LI B, et al. AIC649 in combination with entecavir leads to WHsAg loss in the woodchuck animal model of chronic hepatitis B[J]. Hepatology, 2017, 66:1268A. [53] ADDY I, JAMBRECINA A, BERG T, et al. First in human, single ascending dose clinical trial of AIC649 in patients with chronic hepatitis B[Z]. Wiley 111 River St, Hoboken 07030-5774, NJ USA, 2018:25, 190. [54] LUCIFORA J, BONNIN M, AILLOT L, et al. Direct antiviral properties of TLR ligands against HBV replication in immunecompetent hepatocytes[J]. Sci Rep, 2018, 8(1):5390. [55] WALSH R, HAMMOND R, JACKSON K, et al. PS-160-Effects of SB9200(Inarigivir)therapy on immune responses in patients with chronic hepatitis B[J]. J Hepatol, 2018, 68:s89. [56] KOROLOWICZ KE, IYER RP, CZERWINSKI S, et al. Antiviral efficacy and host innate immunity associated with SB 9200treatment in the woodchuck model of chronic hepatitis B[J].PLoS One, 2016, 11(8):e0161313. [57] CHAN H. Ascending dose cohort study of inarigivir-A novel RIG I agonist in chronic HBV patients:Final results of the ACHIEVE trial[J]. J Hepatol, 2019, 70(1):e47-e48. [58] ABLASSER A, GOLDECK M, CAVLAR T, et al. cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING[J]. Nature, 2013, 498(7454):380-384. [59] THOMSEN MK, NANDAKUMAR R, STADLER D, et al. Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection[J]. Hepatology, 2016, 64(3):746-759. [60] VERRIER ER, YIM SA, HEYDMANN L, et al. Hepatitis B virus evasion from cyclic guanosine monophosphate-adenosine monophosphate synthase sensing in human hepatocytes[J].Hepatology, 2018, 68(5):1695-1709. [61] GUO F, HAN Y, ZHAO X, et al. STING agonists induce an innate antiviral immune response against hepatitis B virus[J].Antimicrob Agents Chemother, 2015, 59(2):1273-1281.
计量
- 文章访问数: 1115
- HTML全文浏览量: 47
- PDF下载量: 269
- 被引次数: 0