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For: Visvanathan K, Skinner NA, Thompson AJV, Riordan SM, Sozzi V, Edwards R, Rodgers S, Kurtovic J, Chang J, Lewin S, Desmond P, Locarnini S. Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology 2007;45:102-10. [PMID: 17187404 DOI: 10.1002/hep.21482] [Citation(s) in RCA: 275] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]

For:	Visvanathan K, Skinner NA, Thompson AJV, Riordan SM, Sozzi V, Edwards R, Rodgers S, Kurtovic J, Chang J, Lewin S, Desmond P, Locarnini S. Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology 2007;45:102-10. [PMID: 17187404 DOI: 10.1002/hep.21482] [Citation(s) in RCA: 275] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]

Number

Cited by Other Article(s)

Chuang YC, Ou JHJ. Effects of cellular membranes and the precore protein on hepatitis B virus core particle assembly and DNA replication. mBio 2025;16:e0397224. [PMID: 40042302 PMCID: PMC11980540 DOI: 10.1128/mbio.03972-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 02/07/2025] [Indexed: 04/10/2025] Open

Abstract

Hepatitis B virus (HBV) core particle is critical for the transport and replication of the viral DNA genome. By characterizing HBV core particles in different subcellular compartments, we found that when the HBV core protein was expressed by itself, it formed core particles with a uniform and fast mobility on a non-denaturing agarose gel. However, when the core protein was expressed from a replication-competent 1.3mer HBV genome, it formed particles with more heterogeneous structures. The presence of the precore protein, a protein related to the core protein, led to the formation of chimeric particles in the cytoplasm that consisted of both precore and core proteins. When the precore protein was expressed by itself, it could also form particulate structures in association with cellular RNAs in the nucleus. Our further analysis revealed that, in cells with replicating HBV, only the fast-migrating core particles on the gel contained the viral RNA and DNA, and the membrane-associated core particles contained more mature HBV DNA than the cytosolic core particles. In addition, the precore protein reduced the level of core particle-associated HBV DNA. Interestingly, the precore protein level in the cells could be increased by the degradative autophagy inhibitor bafilomycin A1 but not by the proteasome inhibitor MG132, suggesting that autophagy might regulate the biological activities of the precore protein. In conclusion, our results indicated that membranes and the precore protein could regulate HBV core particle assembly and DNA replication and suggested a role of autophagy in the regulation of HBV precore protein activities.

IMPORTANCE

Hepatitis B virus (HBV) is an important human pathogen that chronically infects 254 million people in the world. This virus contains a core particle, which plays an important role in the transport and replication of the viral DNA genome. The major protein constituent of this particle is the viral core protein. In this report, we examined how the subcellular compartments and the related precore protein might affect the core particle structure and viral DNA replication. We found that the subcellular localizations could affect the core particle assembly, and membranes and the precore protein could regulate HBV DNA replication. We also found that the inhibition of autophagic degradation increased the precore protein level, suggesting a role of autophagy in the regulation of precore protein activities. These findings provided important information for further understanding the HBV life cycle, which will aid in the development of novel drugs for the treatment of HBV patients.

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Bertoletti A. The immune response in chronic HBV infection. J Viral Hepat 2024;31 Suppl 2:43-55. [PMID: 38845402 DOI: 10.1111/jvh.13962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 05/14/2024] [Indexed: 12/06/2024]

Zheng S, Qi W, Xue T, Zao X, Xie J, Zhang P, Li X, Ye Y, Liu A. Chinese medicine in the treatment of chronic hepatitis B: The mechanisms of signal pathway regulation. Heliyon 2024;10:e39176. [PMID: 39640799 PMCID: PMC11620126 DOI: 10.1016/j.heliyon.2024.e39176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 10/08/2024] [Indexed: 12/07/2024] Open

Echevarria-Lima J, Moles R. Monocyte and Macrophage Functions in Oncogenic Viral Infections. Viruses 2024;16:1612. [PMID: 39459945 PMCID: PMC11512331 DOI: 10.3390/v16101612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 10/07/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open

Wang C, Huang C, Li Y, Bai J, Zhao K, Fang Z, Chen J. Hepatitis B surface antigen impairs TLR4 signaling by upregulating A20 expression in monocytes. Microbiol Spectr 2024;12:e0090924. [PMID: 39248482 PMCID: PMC11448406 DOI: 10.1128/spectrum.00909-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 08/06/2024] [Indexed: 09/10/2024] Open

Abstract

Toll-like receptors (TLRs) play a crucial role in eliminating viral infection. Conversely, viruses have evolved various strategies to disrupt TLR signaling during chronic infection. In the case of hepatitis B virus (HBV), we previously reported that plasma hepatitis B surface antigen (HBsAg) is closely associated with impaired TLR responses in peripheral blood mononuclear cells from chronic hepatitis B (CHB) patients, but the reasons remain unclear. In this study, we investigated the mechanism by which HBsAg suppresses TLR4 signaling in monocyte cell lines. The monocyte cell line THP-1 was pretreated with HBsAg, followed by lipopolysaccharide (LPS) stimulation. Levels of proinflammatory cytokines and the activation of NF-κB, c-JNK, and ERK were examined. We found that HBsAg did not influence the LPS-induced activation of p65, but it disrupted NF-κB promoter activity through the ectopic expression of myeloid differentiation factor 88 (MyD88) and TAK1, suggesting that HBsAg can block downstream TLR4 signaling. Furthermore, we proved that LPS-induced polyubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) and the formation of the TRAF6-TAB2 complex were inhibited in HBsAg-pretreated cells. Interestingly, HBsAg led to a significant upregulation of A20, a ubiquitin-editing enzyme. Correspondingly, downregulation of A20 using siRNA restored LPS-mediated cytokines production, reflecting its crucial role in HBsAg-mediated inhibition of TLR4 signaling. These results demonstrated a novel mechanism by which HBsAg disrupts TLR4 signaling through the upregulation of A20, suggesting that targeting A20 may be a potential strategy to help restore monocyte functions.

IMPORTANCE

Clearance HBsAg indicates a functional cure of HBV infection, but in chronic hepatitis B (CHB), it is hard to achieve. HBsAg has been found to regulate anti-viral immune responses, such as the activation of TLR. Our previous jobs proved that HBsAg negatively correlates with TLR2/4 activation in monocytes from CHB patients and blocks TLR2 ligand-indcuced IL-12 production in monocytes. However, how TLR4 signaling is affected by HBsAg remains unknown. In this study, we not only observed impaired TLR4 activation after pretreated monocytes with HBsAg but also identified HBsAg-induced A20 play a role in this impairment, which suggests that targeting A20 may be a viable strategy to restore monocyte functions in CHB.

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Pondé RADA, Amorim GDSP. Elimination of the hepatitis B virus: A goal, a challenge. Med Res Rev 2024;44:2015-2034. [PMID: 38528684 DOI: 10.1002/med.22030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/24/2024] [Accepted: 02/05/2024] [Indexed: 03/27/2024]

Abstract

The hepatitis B elimination is a goal proposed by the WHO to be achieved by 2030 through the adoption of synergistic measures for the prevention and chronic HBV infection treatment. Complete cure is characterized by the HBV elimination from the body and is the goal of the chronic hepatitis B treatment, which once achieved, will enable the hepatitis B elimination. This, today, has been a scientific challenge. The difficulty in achieving a complete cure is due to the indefinite maintenance of a covalently closed episomal circular DNA (cccDNA) reservoir and the maintenance and persistence of an insufficient and dysfunctional immune response in chronically infected patients. Among the measures adopted to eliminate hepatitis B, two have the potential to directly interfere with the virus cycle, but with limited effect on HBV control. These are conventional vaccines-blocking transmission and antiviral therapy-inhibiting replication. Vaccines, despite their effectiveness in protecting against horizontal transmission and preventing mother-to-child vertical transmission, have no effect on chronic infection or potential to eliminate the virus. Treatment with antivirals suppresses viral replication, but has no curative effect, as it has no action against cccDNA. Therapeutic vaccines comprise an additional approach in the chronic infection treatment, however, they have only a modest effect on the immune system, enhancing it temporarily. This manuscript aims to address (1) the cccDNA persistence in the hepatocyte nucleus and the immune response dysfunction in chronically infected individuals as two primary factors that have hampered the treatment and HBV elimination from the human body; (2) the limitations of antiviral therapy and therapeutic vaccines, as strategies to control hepatitis B; and (3) the possibly promising therapeutic approaches for the complete cure and elimination of hepatitis B.

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Padarath K, Deroubaix A, Naicker P, Stoychev S, Kramvis A. Comparison of the Proteome of Huh7 Cells Transfected with Hepatitis B Virus Subgenotype A1, with or without G1862T. Curr Issues Mol Biol 2024;46:7032-7047. [PMID: 39057060 PMCID: PMC11275860 DOI: 10.3390/cimb46070419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 07/01/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open

Bhat S, Ahanger IA, Kazim SN. Forthcoming Developments in Models to Study the Hepatitis B Virus Replication Cycle, Pathogenesis, and Pharmacological Advancements. ACS OMEGA 2023;8:14273-14289. [PMID: 37125123 PMCID: PMC10134252 DOI: 10.1021/acsomega.2c07154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 02/08/2023] [Indexed: 05/03/2023]

Nevola R, Beccia D, Rosato V, Ruocco R, Mastrocinque D, Villani A, Perillo P, Imbriani S, Delle Femine A, Criscuolo L, Alfano M, La Montagna M, Russo A, Marfella R, Cozzolino D, Sasso FC, Rinaldi L, Marrone A, Adinolfi LE, Claar E. HBV Infection and Host Interactions: The Role in Viral Persistence and Oncogenesis. Int J Mol Sci 2023;24:7651. [PMID: 37108816 PMCID: PMC10145402 DOI: 10.3390/ijms24087651] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/14/2023] [Accepted: 04/19/2023] [Indexed: 04/29/2023] Open

Affiliation(s)

Riccardo Nevola Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (D.M.); (P.P.); (E.C.) Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Domenico Beccia Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Valerio Rosato Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (D.M.); (P.P.); (E.C.)
Rachele Ruocco Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Davide Mastrocinque Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (D.M.); (P.P.); (E.C.)
Angela Villani Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Pasquale Perillo Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (D.M.); (P.P.); (E.C.)
Simona Imbriani Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Augusto Delle Femine Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Livio Criscuolo Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Maria Alfano Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Marco La Montagna Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Antonio Russo Department of Mental Health and Public Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
Raffaele Marfella Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Domenico Cozzolino Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Ferdinando Carlo Sasso Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Luca Rinaldi Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Aldo Marrone Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Luigi Elio Adinolfi Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
Ernesto Claar Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (D.M.); (P.P.); (E.C.)

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Padarath K, Deroubaix A, Kramvis A. The Complex Role of HBeAg and Its Precursors in the Pathway to Hepatocellular Carcinoma. Viruses 2023;15:v15040857. [PMID: 37112837 PMCID: PMC10144019 DOI: 10.3390/v15040857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023] Open

Maciel-Fiuza MF, Muller GC, Campos DMS, do Socorro Silva Costa P, Peruzzo J, Bonamigo RR, Veit T, Vianna FSL. Role of gut microbiota in infectious and inflammatory diseases. Front Microbiol 2023;14:1098386. [PMID: 37051522 PMCID: PMC10083300 DOI: 10.3389/fmicb.2023.1098386] [Citation(s) in RCA: 66] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 03/06/2023] [Indexed: 03/29/2023] Open

Affiliation(s)

Miriãn Ferrão Maciel-Fiuza Postgraduate Program in Genetics and Molecular Biology, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil Instituto Nacional de Genética Médica Populacional, Porto Alegre, Brazil Genomics Medicine Laboratory, Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
Guilherme Cerutti Muller Postgraduate Program in Genetics and Molecular Biology, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
Daniel Marques Stuart Campos Genomics Medicine Laboratory, Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
Perpétua do Socorro Silva Costa Postgraduate Program in Genetics and Molecular Biology, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil Instituto Nacional de Genética Médica Populacional, Porto Alegre, Brazil Department of Nursing, Universidade Federal do Maranhão, Imperatriz, Brazil
Juliano Peruzzo Dermatology Service of Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil Postgraduate Program in Medicine, Medical Sciences, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
Renan Rangel Bonamigo Dermatology Service of Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil Postgraduate Program in Medicine, Medical Sciences, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil Postgraduate Program in Pathology, Universidade Federal De Ciências Da Saúde de Porto Alegre, Porto Alegre, Brazil
Tiago Veit Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil Department of Microbiology, Immunology and Parasitology, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
Fernanda Sales Luiz Vianna Postgraduate Program in Genetics and Molecular Biology, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil Instituto Nacional de Genética Médica Populacional, Porto Alegre, Brazil Genomics Medicine Laboratory, Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil Postgraduate Program in Medicine, Medical Sciences, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil *Correspondence: Fernanda Sales Luiz Vianna,

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Mak LY, Hui RWH, Cheung KS, Fung J, Seto WK, Yuen MF. Advances in determining new treatments for hepatitis B infection by utilizing existing and novel biomarkers. Expert Opin Drug Discov 2023;18:401-416. [PMID: 36943183 DOI: 10.1080/17460441.2023.2192920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]

Farnesoid X Receptor Activation Decreases Toll-like Receptor 2 Expression by Upregulating HBeAg Production. HEPATITIS MONTHLY 2023. [DOI: 10.5812/hepatmon-129128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]

Chen X, Liu X, Jiang Y, Xia N, Liu C, Luo W. Abnormally primed CD8 T cells: The Achilles' heel of CHB. Front Immunol 2023;14:1106700. [PMID: 36936922 PMCID: PMC10014547 DOI: 10.3389/fimmu.2023.1106700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 02/20/2023] [Indexed: 03/05/2023] Open

Affiliation(s)

Xiaoqing Chen State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
Xue Liu State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
Yichao Jiang State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
Ningshao Xia State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China Xiang An Biomedicine Laboratory, Xiamen, Fujian, China The Research Unit of Frontier Technology of Structural Vaccinology, Chinese Academy of Medical Sciences, Xiamen, Fujian, China
Chao Liu State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China *Correspondence: Wenxin Luo, ; Chao Liu,
Wenxin Luo State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China Xiang An Biomedicine Laboratory, Xiamen, Fujian, China *Correspondence: Wenxin Luo, ; Chao Liu,

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Hall SAL, Burns GS, Mooney BJ, Millen R, Morris R, Vogrin S, Sundararajan V, Ratnam D, Levy MT, Lubel JS, Nicoll AJ, Strasser SI, Sievert W, Desmond PV, Ngu MC, Angus P, Sinclair M, Meredith C, Matthews G, Revill PA, Jackson K, Littlejohn M, Bowden S, Locarnini SA, Thompson AJ, Visvanathan K. Hepatitis B Virus Flares After Nucleot(s)ide Analogue Cessation Are Associated With Activation of Toll-Like Receptor Signaling Pathways. J Infect Dis 2022;227:123-132. [PMID: 36108079 DOI: 10.1093/infdis/jiac375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 09/02/2022] [Accepted: 09/13/2022] [Indexed: 01/19/2023] Open

Affiliation(s)

Samuel A L Hall Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
Gareth S Burns Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
Benjamin J Mooney Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
Rosemary Millen Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
Rachel Morris Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
Sara Vogrin Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
Vijaya Sundararajan The Department of Public Health, La Trobe University, Melbourne, Australia
Dilip Ratnam Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Australia
Miriam T Levy Gastroenterology Department of Liverpool Hospital, Sydney, Australia
John S Lubel Department of Gastroenterology, Alfred Health, Melbourne, Australia Central Clinical School, Monash University, The Alfred Centre, Melbourne, Australia
Amanda J Nicoll Gastroenterology Department of Eastern Health, Melbourne, Australia
Simone I Strasser AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia Faculty of Medicine and Health, University of Sydney, Sydney, Australia
William Sievert Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Australia Department of Medicine, Monash University, Melbourne, Australia
Paul V Desmond Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
Meng C Ngu Gastroenterology Department of Concord Repatriation General Hospital, Sydney, Australia
Peter Angus Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
Marie Sinclair Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia
Christopher Meredith Gastroenterology Department of Bankstown-Lidcombe Hospital, Sydney, Australia
Gail Matthews Department of infectious Disease, St Vincent's Hospital Sydney, SydneyAustralia
Peter A Revill Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
Kathy Jackson Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
Margaret Littlejohn Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
Scott Bowden Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
Stephen A Locarnini Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
Alexander J Thompson Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
Kumar Visvanathan Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia

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Hatton AA, Guerra FE. Scratching the Surface Takes a Toll: Immune Recognition of Viral Proteins by Surface Toll-like Receptors. Viruses 2022;15:52. [PMID: 36680092 PMCID: PMC9863796 DOI: 10.3390/v15010052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 12/22/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022] Open

Multifaceted Defects in Monocytes in Different Phases of Chronic Hepatitis B Virus Infection: Lack of Restoration after Antiviral Therapy. Microbiol Spectr 2022;10:e0193922. [PMID: 36445121 PMCID: PMC9769680 DOI: 10.1128/spectrum.01939-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open

Abstract

Monocytes play an important role in the control of microbial infection, but monocyte biology during chronic hepatitis B virus (HBV) infection (CHI) remains inadequately studied. We investigated the frequency, phenotype, and functions of monocyte subsets in different phases of CHI, namely, immune tolerance (IT), hepatitis B early antigen (HBeAg)-positive/HBeAg-negative chronic hepatitis B (EP-/EN-CHB, respectively), and inactive carrier (IC), identified factors responsible for their functional alterations, and determined the impact of antiviral therapy on these cells. Flow cytometric analysis indicated that HLA-DR⁺ CD14⁺⁺ CD16^- classical monocytes were significantly reduced while HLA-DR⁺ CD14⁺⁺ CD16⁺ intermediate and HLA-DR⁺ CD14⁺ CD16⁺⁺ nonclassical monocytes were expanded in IT and EP-/EN-CHB compared with those in IC and healthy controls (HC). In comparison to IC/HC, monocytes in IT and CHB exhibited diminished expression of Toll-like receptor 2 (TLR-2)/TLR-4/TLR-9 and cytokines interleukin-12 (IL-12)/tumor necrosis factor alpha (TNF-α)/IL-6 but produced higher levels of IL-10/transforming growth factor β (TGF-β). Further, monocytes in CHB/IT showed impaired phagocytosis and oxidative response relative to those in IC/HC. In vitro assays indicated that high titers of hepatitis B surface antigen (HBsAg) present in IT/CHB and of IL-4 in CHB triggered the functional defects in monocytes via induction of β-catenin. Additionally, monocyte-derived M1 macrophages of CHB/IT produced fewer proinflammatory and more anti-inflammatory cytokines than those of IC/HC, while in CHB/IT, the monocytes skewed the differentiation of CD4⁺ T cells more toward regulatory T cells and a Th2 phenotype. Moreover, monocytes in CHB and IT overexpressed chemokine receptor CCR2, which coincided with increased intrahepatic accumulation of β-catenin⁺ CD14⁺ cells. One year of tenofovir therapy failed to normalize monocyte functions or reduce serum HBsAg/IL-4 levels. Taken together, monocytes are functionally perturbed mostly in IT and EP-/EN-CHB phases. Targeting intramonocytic β-catenin or reducing HBsAg/IL-4 levels might restore monocyte function and facilitate viral clearance. IMPORTANCE Chronic HBV infection (CHI) is a major cause of end-stage liver disease for which pharmacological treatments currently available are inadequate. Chronically HBV-infected patients fail to mount an efficient immune response to the virus, impeding viral clearance and recovery from hepatitis. Monocytes represent a central part of innate immunity, but a comprehensive understanding on monocyte involvement in CHI is still lacking. We here report a multitude of defects in monocytes in chronically HBV-infected patients that include alteration in subset distribution, Toll-like receptor expression, cytokine production, phagocytic activity, oxidative response, migratory ability, polarization of monocyte-derived macrophages, and monocyte-T-cell interaction. We demonstrated that high levels of hepatitis B virus surface antigen and IL-4 potentiate these defects in monocytes via β-catenin induction while therapy with the nucleotide analog tenofovir fails to restore monocyte function. Our findings add to the continuing effort to devise new immunotherapeutic strategies that could reverse the immune defects in CHI.

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Jin X, Bi J. Prospects for NK-based immunotherapy of chronic HBV infection. Front Immunol 2022;13:1084109. [PMID: 36591230 PMCID: PMC9797727 DOI: 10.3389/fimmu.2022.1084109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 12/01/2022] [Indexed: 12/16/2022] Open

Ohlendorf V, Wübbolding M, Gineste P, Höner Zu Siederdissen C, Bremer B, Wedemeyer H, Cornberg M, Maasoumy B. Low anti-HBc levels are associated with lower risk of virological relapse after nucleos(t)ide analogue cessation in HBe antigen-negative patients. Liver Int 2022;42:2674-2682. [PMID: 36152268 DOI: 10.1111/liv.15433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/25/2022] [Accepted: 09/06/2022] [Indexed: 12/13/2022]

Yang G, Wan P, Zhang Y, Tan Q, Qudus MS, Yue Z, Luo W, Zhang W, Ouyang J, Li Y, Wu J. Innate Immunity, Inflammation, and Intervention in HBV Infection. Viruses 2022;14:2275. [PMID: 36298831 PMCID: PMC9609328 DOI: 10.3390/v14102275] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/12/2022] [Accepted: 10/15/2022] [Indexed: 07/30/2023] Open

Desmares M, Delphin M, Chardès B, Pons C, Riedinger J, Michelet M, Rivoire M, Verrier B, Salvetti A, Lucifora J, Durantel D. Insights on the antiviral mechanisms of action of the TLR1/2 agonist Pam3CSK4 in hepatitis B virus (HBV)-infected hepatocytes. Antiviral Res 2022;206:105386. [PMID: 35963549 DOI: 10.1016/j.antiviral.2022.105386] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 07/20/2022] [Accepted: 07/23/2022] [Indexed: 12/31/2022]

Abstract

OBJECTIVES

Pegylated-interferon-alpha (Peg-IFNα), an injectable innate immune protein, is still used to treat chronically HBV-infected patients, despite its poor tolerability. Peg-IFNα has the advantage over nucleos(t)ide analogues (NAs) to be administrated in finite regimen and to lead to a higher HBsAg loss rate. Yet it would be interesting to improve the efficacy (i.e. while decreasing doses), or replace, this old medicine by novel small molecules/stimulators able to engage innate immune receptors in both HBV replicating hepatocytes and relevant innate immune cells. We have previously identified the Toll-Like-Receptor (TLR)-2 agonist Pam3CSK4 as such a potential novel immune stimulator. The aim of this study was to gain insights on the antiviral mechanisms of action of this agonist in in vitro cultivated human hepatocytes.

DESIGN

We used in vitro models of HBV-infected cells, based on both primary human hepatocytes (PHH) and the non-transformed HepaRG cell line to investigate the MoA of Pam3SCK4 and identify relevant combinations with other approved or investigational drugs.

RESULTS

We exhaustively described the inhibitory anti-HBV phenotypes induced by Pam3CSK4, which include a strong decrease in HBV RNA production (inhibition of synthesis and acceleration of decay) and cccDNA levels. We confirmed the long-lasting anti-HBV activity of this agonist, better described the kinetics of antiviral events, and demonstrated the specificity of action through the TLR1/2- NF-κB canonical-pathway. Moreover, we found that FEN-1 could be involved in the regulation and inhibitory phenotype on cccDNA levels. Finally, we identified the combination of Pam3CSK4 with IFNα or an investigational kinase inhibitor (called 1C8) as valuable strategies to reduce cccDNA levels and obtain a long-lasting anti-HBV effect in vitro.

CONCLUSIONS

TLR2 agonists represent possible assets to improve the rate of HBV cure in patients. Further evaluations, including regulatory toxicity studies, are warranted to move toward clinical trials.

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Affiliation(s)

Manon Desmares INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
Marion Delphin INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
Brieux Chardès INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
Caroline Pons INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; INSERM, U1111, Centre International de Recherche en Infectiologie (CIRI), University of Lyon (UCBL1), CNRS UMR_5308, ENS de Lyon, Lyon, France
Juliette Riedinger INSERM, U1111, Centre International de Recherche en Infectiologie (CIRI), University of Lyon (UCBL1), CNRS UMR_5308, ENS de Lyon, Lyon, France
Maud Michelet INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
Michel Rivoire INSERM U1032, Centre Léon Bérard (CLB), Lyon, France
Bernard Verrier Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique, CNRS UMR_5305, University of Lyon (UCBL1), Lyon, France
Anna Salvetti INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; INSERM, U1111, Centre International de Recherche en Infectiologie (CIRI), University of Lyon (UCBL1), CNRS UMR_5308, ENS de Lyon, Lyon, France
Julie Lucifora INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; INSERM, U1111, Centre International de Recherche en Infectiologie (CIRI), University of Lyon (UCBL1), CNRS UMR_5308, ENS de Lyon, Lyon, France
David Durantel INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; INSERM, U1111, Centre International de Recherche en Infectiologie (CIRI), University of Lyon (UCBL1), CNRS UMR_5308, ENS de Lyon, Lyon, France.

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Bhat S, Kazim SN. HBV cccDNA-A Culprit and Stumbling Block for the Hepatitis B Virus Infection: Its Presence in Hepatocytes Perplexed the Possible Mission for a Functional Cure. ACS OMEGA 2022;7:24066-24081. [PMID: 35874215 PMCID: PMC9301636 DOI: 10.1021/acsomega.2c02216] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]

Abstract

Hepatitis B virus infection (HBV) is still a big health problem across the globe. It has been linked to the development of liver cirrhosis and hepatocellular carcinoma and can trigger different types of liver damage. Existing medicines are unable to disable covalently closed circular DNA (cccDNA), which may result in HBV persistence and recurrence. The current therapeutic goal is to achieve a functional cure, which means HBV-DNA no longer exists when treatment stops and the absence of HBsAg seroclearance. However, due to the presence of integrated HBV DNA and cccDNA functional treatment is now regarded to be difficult. In order to uncover pathways for potential therapeutic targets and identify medicines that could result in large rates of functional cure, a thorough understanding of the virus' biology is required. The proteins of the virus and episomal cccDNA are thought to be critical for the management and support of the HBV replication cycle as they interact directly with the host proteome to establish the best atmosphere for the virus while evading immune detection. The breakthroughs of host dependence factors, cccDNA transcription, epigenetic regulation, and immune-mediated breakdown have all produced significant progress in our understanding of cccDNA biology during the past decade. There are some strategies where cccDNA can be targeted either in a direct or indirect way and are presently at the point of discovery or preclinical or early clinical advancement. Editing of genomes, techniques targeting host dependence factors or epigenetic gene maintenance, nucleocapsid modulators, miRNA, siRNA, virion secretory inhibitors, and immune-mediated degradation are only a few examples. Though cccDNA approaches for direct targeting are still in the early stages of development, the assembly of capsid modulators and immune-reliant treatments have made it to the clinic. Clinical trials are currently being conducted to determine their efficiency and safety in patients, as well as their effect on viral cccDNA. The influence of recent breakthroughs in the development of new treatment techniques on cccDNA biology is also summarized in this review.

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Association of Toll-Like Receptor 2 (TLR2) Expression in Placenta and Intrauterine Exposure to Hepatitis B Virus. Interdiscip Perspect Infect Dis 2022;2022:4838376. [PMID: 35875205 PMCID: PMC9300366 DOI: 10.1155/2022/4838376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 06/15/2022] [Accepted: 06/20/2022] [Indexed: 11/18/2022] Open

Phillips S, Jagatia R, Chokshi S. Novel therapeutic strategies for Chronic Hepatitis B. Virulence 2022;13:1111-1132. [PMID: 35763282 PMCID: PMC9272843 DOI: 10.1080/21505594.2022.2093444] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open

Wildum S, Korolowicz KE, Suresh M, Steiner G, Dai L, Li B, Yon C, De Vera Mudry MC, Regenass-Lechner F, Huang X, Hong X, Murreddu MG, Kallakury BV, Young JAT, Menne S. Toll-Like Receptor 7 Agonist RG7854 Mediates Therapeutic Efficacy and Seroconversion in Woodchucks With Chronic Hepatitis B. Front Immunol 2022;13:884113. [PMID: 35677037 PMCID: PMC9169629 DOI: 10.3389/fimmu.2022.884113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/22/2022] [Indexed: 01/04/2023] Open

Abstract

Conventional treatment of chronic hepatitis B (CHB) is rarely curative due to the immunotolerant status of patients. RG7854 is an oral double prodrug of a toll-like receptor 7 (TLR7) agonist that is developed for the treatment of CHB. The therapeutic efficacy, host immune response, and safety of RG7854 were evaluated in the woodchuck model of CHB. Monotreatment with the two highest RG7854 doses and combination treatment with the highest RG7854 dose and entecavir (ETV) suppressed viral replication, led to loss of viral antigens, and induced seroconversion in responder woodchucks. Since viral suppression and high-titer antibodies persisted after treatment ended, this suggested that a sustained antiviral response (SVR) was induced by RG7854 in a subset of animals. The SVR rate, however, was comparable between both treatment regimens, suggesting that the addition of ETV did not enhance the therapeutic efficacy of RG7854 although it augmented the proliferation of blood cells in response to viral antigens and magnitude of antibody titers. The induction of interferon-stimulated genes in blood by RG7854/ETV combination treatment demonstrated on-target activation of TLR7. Together with the virus-specific blood cell proliferation and the transient elevations in liver enzymes and inflammation, this suggested that cytokine-mediated non-cytolytic and T-cell mediated cytolytic mechanisms contributed to the SVR, in addition to the virus-neutralizing effects by antibody-producing plasma cells. Both RG7854 regimens were not associated with treatment-limiting adverse effects but accompanied by dose-dependent, transient neutropenia and thrombocytopenia. The study concluded that finite, oral RG7854 treatment can induce a SVR in woodchucks that is based on the retrieval of antiviral innate and adaptive immune responses. This supports future investigation of the TLR7 agonist as an immunotherapeutic approach for achieving functional cure in patients with CHB.

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Zaki MYW, Fathi AM, Samir S, Eldafashi N, William KY, Nazmy MH, Fathy M, Gill US, Shetty S. Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma. Cancers (Basel) 2022;14:1255. [PMID: 35267563 PMCID: PMC8909759 DOI: 10.3390/cancers14051255] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/01/2022] [Accepted: 02/04/2022] [Indexed: 02/08/2023] Open

You H, Qin S, Zhang F, Hu W, Li X, Liu D, Kong F, Pan X, Zheng K, Tang R. Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection. Front Immunol 2022;13:829923. [PMID: 35251017 PMCID: PMC8891514 DOI: 10.3389/fimmu.2022.829923] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/24/2022] [Indexed: 12/16/2022] Open

Humoral immunity in hepatitis B virus infection: Rehabilitating the B in HBV. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022;4:100398. [PMID: 35059620 PMCID: PMC8760517 DOI: 10.1016/j.jhepr.2021.100398] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 12/15/2022]

Nosaka T, Naito T, Murata Y, Matsuda H, Ohtani M, Hiramatsu K, Nishizawa T, Okamoto H, Nakamoto Y. Regulatory function of interferon-inducible 44-like for hepatitis B virus covalently closed circular DNA in primary human hepatocytes. Hepatol Res 2022;52:141-152. [PMID: 34697871 DOI: 10.1111/hepr.13722] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 10/13/2021] [Accepted: 10/17/2021] [Indexed: 12/12/2022]

Xie X, Luo J, Zhu D, Zhou W, Yang X, Feng X, Lu M, Zheng X, Dittmer U, Yang D, Liu J. HBeAg Is Indispensable for Inducing Liver Sinusoidal Endothelial Cell Activation by Hepatitis B Virus. Front Cell Infect Microbiol 2022;12:797915. [PMID: 35174107 PMCID: PMC8842949 DOI: 10.3389/fcimb.2022.797915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 01/11/2022] [Indexed: 11/13/2022] Open

Chuang YC, Tsai KN, Ou JHJ. Pathogenicity and virulence of Hepatitis B virus. Virulence 2022;13:258-296. [PMID: 35100095 PMCID: PMC8812780 DOI: 10.1080/21505594.2022.2028483] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open

Werner M, Schefczyk S, Trippler M, Treckmann JW, Baba HA, Gerken G, Schlaak JF, Broering R. Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3. Viruses 2022;14:218. [PMID: 35215812 PMCID: PMC8874605 DOI: 10.3390/v14020218] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 02/06/2023] Open

Affiliation(s)

Melanie Werner Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
Stefan Schefczyk Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
Martin Trippler Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
Juergen W. Treckmann Department of General-, Visceral- and Transplantation-Surgery, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany;
Hideo A. Baba Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany;
Guido Gerken Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.) Helios Hospital, Gastroenterology, Hepatology and Palliative Medicine, Robert-Koch-Straße 2, 42549 Velbert, Germany
Joerg F. Schlaak Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.) AMEOS Hospital, St. Clemens, Internal Medicine—Hepatology, Gastroenterology, Infectiology and Diabetology, Wilhelmstr. 34, 46145 Oberhausen, Germany
Ruth Broering Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)

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Naghib M, Kariminik A, Kazemi Arababadi M. TLR2, as a Pathogen Recognition Receptor, Plays Critical Roles in Hepatitis B Outcome. Viral Immunol 2022;35:15-23. [PMID: 35020525 DOI: 10.1089/vim.2021.0141] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open

Kostyusheva A, Brezgin S, Glebe D, Kostyushev D, Chulanov V. Host-cell interactions in HBV infection and pathogenesis: the emerging role of m6A modification. Emerg Microbes Infect 2021;10:2264-2275. [PMID: 34767497 PMCID: PMC8648018 DOI: 10.1080/22221751.2021.2006580] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/08/2021] [Accepted: 11/10/2021] [Indexed: 12/28/2022]

Zábranská H, Zábranský A, Lubyová B, Hodek J, Křenková A, Hubálek M, Weber J, Pichová I. Biogenesis of hepatitis B virus e antigen is driven by translocon-associated protein complex and regulated by conserved cysteine residues within its signal peptide sequence. FEBS J 2021;289:2895-2914. [PMID: 34839586 PMCID: PMC9300162 DOI: 10.1111/febs.16304] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/27/2021] [Accepted: 11/26/2021] [Indexed: 11/28/2022]

Insufficient immunity led to virologic breakthrough in NAs-treated chronic hepatitis B patients switching to Peg-IFN-ɑ. Antiviral Res 2021;197:105220. [PMID: 34848218 DOI: 10.1016/j.antiviral.2021.105220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/16/2021] [Accepted: 11/25/2021] [Indexed: 11/24/2022]

Abstract

BACKGROUND

Virologic breakthrough (VBT) may occur in chronic hepatitis B (CHB) patients after switching from nucleos(t)ide analogues (NAs) to pegylated interferon alpha (Peg-IFN-ɑ). This study aimed to characterize the clinical and immunological features of VBT.

METHODS

In NAs-treated patients switching to Peg-IFN-ɑ, innate and adaptive immune cell proportions were examined in peripheral blood and liver biopsy specimens. In vitro effect of IFN-ɑ on the expressions of toll-like receptors 2 (TLR2) and programmed cell death ligand 1 (PDL1) on monocytes, programmed cell death 1 (PD1) on CD8⁺T cells was examined. Peripheral blood mononuclear cells (PBMCs) were treated with TLR2 agonist and/or PDL1 blockade to evaluate their effect on HBV replication.

RESULTS

33 of 166 patients switching to Peg-IFN-ɑ experienced VBT after NA cessation, with majority being hepatitis B e antigen (HBeAg) positive or having higher hepatitis B core-related antigen (HBcrAg) levels. Patients with VBT exhibited lower proportions of TLR2⁺monocyte and increased PD1⁺HBV-specific CD8⁺T cell during the early phase of Peg-IFN-ɑ therapy after NA cessation in peripheral blood, as well as fewer TLR2⁺CD68⁺macrophages but more PDL1⁺CD68⁺macrophages and PD1⁺CD8⁺T cells in liver tissues. Simultaneous use of TLR2 agonist and PDL1 blockage ex vivo suppressed HBV replication by promoting cytokines production and CD8⁺T cells cytotoxicity. Upon in vitro IFN-ɑ stimulation, PDL1⁺monocytes and PD1⁺CD8⁺T cells were upregulated, whereas TLR2⁺monocytes were not increased in PBMC isolated from HBeAg-positive patients, or those with high HBcrAg titers.

CONCLUSIONS

In NAs-treated patients, lower TLR2⁺monocyte and increased PD1⁺HBV-specific CD8⁺T cell proportions potentially contribute to VBT after switching to Peg-IFN-ɑ therapy. This insufficient immunity may be associated with the HBeAg status and HBcrAg levels.

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Getachew A, Hussain M, Huang X, Li Y. Toll-like receptor 2 signaling in liver pathophysiology. Life Sci 2021;284:119941. [PMID: 34508761 DOI: 10.1016/j.lfs.2021.119941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 08/19/2021] [Accepted: 08/30/2021] [Indexed: 12/24/2022]

Affiliation(s)

Anteneh Getachew Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
Muzammal Hussain Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
Xinping Huang Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
Yinxiong Li Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China.

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Delphin M, Desmares M, Schuehle S, Heikenwalder M, Durantel D, Faure-Dupuy S. How to get away with liver innate immunity? A viruses' tale. Liver Int 2021;41:2547-2559. [PMID: 34520597 DOI: 10.1111/liv.15054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 08/20/2021] [Accepted: 09/08/2021] [Indexed: 12/24/2022]

Tsai KN, Ou JHJ. Hepatitis B virus e antigen and viral persistence. Curr Opin Virol 2021;51:158-163. [PMID: 34717215 PMCID: PMC8643334 DOI: 10.1016/j.coviro.2021.10.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 08/27/2021] [Accepted: 10/07/2021] [Indexed: 02/08/2023]

De Pasquale C, Campana S, Pollicino T, Ferlazzo G. REPLY. Hepatology 2021;74:2326-2327. [PMID: 34107084 DOI: 10.1002/hep.32004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]

van Bömmel F, Berg T. Risks and Benefits of Discontinuation of Nucleos(t)ide Analogue Treatment: A Treatment Concept for Patients With HBeAg-Negative Chronic Hepatitis B. Hepatol Commun 2021;5:1632-1648. [PMID: 34558833 PMCID: PMC8485892 DOI: 10.1002/hep4.1708] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/29/2021] [Accepted: 02/15/2021] [Indexed: 12/11/2022] Open

Abstract

Systematic discontinuation of long-term treatment with nucleos(t)ide analogues (NAs) is one strategy to increase functional cure rates in patients with chronic hepatitis B e antigen (HBeAg)-negative hepatitis B. Currently, available study results are heterogeneous; however, long-term hepatitis B surface antigen (HBsAg) loss rates of up to 20% have been reported in prospective trials. This review proposes criteria that can be used when considering NA discontinuation in patients with chronic hepatitis B virus (HBV). Discontinuing NA treatment frequently results in a virologic and biochemical relapse that runs through different phases: the lag phase, reactivation phase, and consolidation phase. The HBV-DNA flares observed during the reactivation phase are often transient and most likely represent a trigger for inducing a long-term immune control by specific CD8+ T cells, and therefore do not need immediate interventions but close follow-up evaluation. Low HBsAg levels at the time of treatment cessation predict a positive long-term response to NA discontinuation associated with a higher likelihood of HBsAg clearance. Other host and viral biomarkers are currently under evaluation that may prove to be helpful to further characterize the population that may benefit most from the finite NA treatment concept. Potential harmful biochemical flares during the reactivation phase need to be identified early and can be effectively terminated by reintroducing NA treatment. Hepatic decompensation represents a risk to patients with cirrhosis undergoing NA discontinuation. Therefore, the finite NA approach should only be considered after excluding advanced fibrosis and cirrhosis and if a close follow-up of the patient and supervision by an experienced physician can be guaranteed. Conclusion: For selected patients, NA discontinuation has become a powerful tool to achieve control over HBeAg-negative HBV infections. Its significant effect represents a challenge to novel treatment approaches, but it may also serve as their enhancer.

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Kayesh MEH, Kohara M, Tsukiyama-Kohara K. Toll-Like Receptor Response to Hepatitis B Virus Infection and Potential of TLR Agonists as Immunomodulators for Treating Chronic Hepatitis B: An Overview. Int J Mol Sci 2021;22:10462. [PMID: 34638802 PMCID: PMC8508807 DOI: 10.3390/ijms221910462] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/26/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open

Ye J, Chen J. Interferon and Hepatitis B: Current and Future Perspectives. Front Immunol 2021;12:733364. [PMID: 34557195 PMCID: PMC8452902 DOI: 10.3389/fimmu.2021.733364] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022] Open

Liu L, Wang Y, Zhang J, Wang C, Li Y, Dai W, Piao C, Liu J, Yu H, Li X, Wang Y, Liu J. Probiotics in treating with alcoholic liver disease and nonalcoholic fatty liver disease. FOOD REVIEWS INTERNATIONAL 2021. [DOI: 10.1080/87559129.2021.1967380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]

Affiliation(s)

Lingchong Liu College of Food Science and Engineering, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China College of Life Science, Changchun Sci-Tech University, Changchun, China
Yu Wang College of Food Science and Engineering, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
Jing Zhang College of Food Science and Engineering, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
Chao Wang College of Food Science and Engineering, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
Youbao Li College of Food Science and Engineering, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, National Processing Laboratory for Soybean Industry and Technology, Changchun, China Department of Food Science and Engineering, National Engineering Laboratory for Wheat and Corn Deep Processing, Changchun, China
Weichang Dai College of Food Science and Engineering, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, National Processing Laboratory for Soybean Industry and Technology, Changchun, China Department of Food Science and Engineering, National Engineering Laboratory for Wheat and Corn Deep Processing, Changchun, China
Chunhong Piao College of Food Science and Engineering, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, National Processing Laboratory for Soybean Industry and Technology, Changchun, China Department of Food Science and Engineering, National Engineering Laboratory for Wheat and Corn Deep Processing, Changchun, China
Junmei Liu College of Food Science and Engineering, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, National Processing Laboratory for Soybean Industry and Technology, Changchun, China Department of Food Science and Engineering, National Engineering Laboratory for Wheat and Corn Deep Processing, Changchun, China
Hansong Yu College of Food Science and Engineering, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, National Processing Laboratory for Soybean Industry and Technology, Changchun, China Department of Food Science and Engineering, National Engineering Laboratory for Wheat and Corn Deep Processing, Changchun, China
Xia Li College of Food Science and Engineering, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, National Processing Laboratory for Soybean Industry and Technology, Changchun, China Department of Food Science and Engineering, National Engineering Laboratory for Wheat and Corn Deep Processing, Changchun, China
Yuhua Wang College of Food Science and Engineering, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, National Processing Laboratory for Soybean Industry and Technology, Changchun, China Department of Food Science and Engineering, National Engineering Laboratory for Wheat and Corn Deep Processing, Changchun, China
Jingsheng Liu College of Food Science and Engineering, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China Department of Food Science and Engineering, National Processing Laboratory for Soybean Industry and Technology, Changchun, China Department of Food Science and Engineering, National Engineering Laboratory for Wheat and Corn Deep Processing, Changchun, China

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Wu LL, Huang TS, Shyu YC, Wang CL, Wang HY, Chen PJ. Gut microbiota in the innate immunity against hepatitis B virus - implication in age-dependent HBV clearance. Curr Opin Virol 2021;49:194-202. [PMID: 34242953 DOI: 10.1016/j.coviro.2021.06.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/16/2021] [Accepted: 06/17/2021] [Indexed: 02/08/2023]

Affiliation(s)

Li-Ling Wu Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taiwan
Ting-Shuo Huang Department of General Surgery, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
Yu-Chiau Shyu Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; Department of Nursing, Chang Gung University of Science and Technology, Taoyuan City, Taiwan; Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
Chih-Lin Wang Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
Hurng-Yi Wang Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Institute of Ecology and Evolutionary Biology, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.
Pei-Jer Chen Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Department of Microbiology, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.

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Vaillant A. HBsAg, Subviral Particles, and Their Clearance in Establishing a Functional Cure of Chronic Hepatitis B Virus Infection. ACS Infect Dis 2021;7:1351-1368. [PMID: 33302622 DOI: 10.1021/acsinfecdis.0c00638] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]

Yao J, Lin C, Jiang J, Zhang X, Li F, Liu T, Diao H. lncRNA-HEIM Facilitated Liver Fibrosis by Up-Regulating TGF-β Expression in Long-Term Outcome of Chronic Hepatitis B. Front Immunol 2021;12:666370. [PMID: 34168644 PMCID: PMC8217658 DOI: 10.3389/fimmu.2021.666370] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/18/2021] [Indexed: 12/26/2022] Open

Abstract

Background

Chronic liver fibrosis is an inevitable stage for the development of patients with chronic hepatitis B (CHB). However, anti-fibrotic therapies have been unsuccessful so far. The biological functions and molecular mechanisms of long non-coding RNAs (lncRNAs) in the host immune system during chronic hepatitis B virus (HBV) infection, especially in fibrosis, are still largely unknown.

Method

The total RNA of peripheral blood mononuclear cells (PBMCs) from asymptomatic carriers (ASCs) or CHB receiving at least 8 years of anti-viral treatments was analyzed using Arraystar microarray and validated via quantitative real-time PCR (qRT-PCR). Correlation analysis was conducted based on correlation coefficients, Clusterprofile, and RNA Interactome Database (RAID). The functions of lncRNA in monocytes were determined via loss-of-function RNAi or gain-of-function lentivirus assays. The expression levels of mRNAs or proteins were evaluated using qRT-PCR, western blotting assay, or enzyme linked immunosorbent assays (ELISA).

Results

A total of 1,042 mRNA transcripts (630 up-regulated and 412 down-regulated) were identified being differentially expressed between ASC and CHB patients. Through enrichment analysis we focused on the transforming growth factor beta (TGF-β) signaling pathway and validated their expression in a larger cohort. Moreover, we found that lncRNA ENST00000519726 (lncRNA-HEIM) was highly expressed in monocytes and further up-regulated upon HBV infection. LncRNA-HEIM played an important role in CHB patients with long-term antiviral treatments, and its elevated expression was remarkably correlated with the TGF-β signaling pathway, especially with the two members namely TGF-β and SMAD4. Furthermore, altering the endogenous lncRNA-HEIM level in monocytes significantly affected the production of TGF-β, as well as the fibrosis of hepatic stellate cells by affecting the expression of collagen I and α-smooth muscle actin (α-SMA).

Conclusion

These findings not only added knowledge to the understanding of the roles of which lncRNA-HEIM played in the activation of HSCs in CHB patients with long-term medication, but also provided a promising therapeutic target in the future treatment for liver fibrosis.

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Affiliation(s)

Jian Yao State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Chenhong Lin State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Jingjing Jiang State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Xujun Zhang State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Fengxia Li State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Tianxing Liu Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
Hongyan Diao State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China

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Tsai TY, Huang MT, Sung PS, Peng CY, Tao MH, Yang HI, Chang WC, Yang AS, Yu CM, Lin YP, Bau CY, Huang CJ, Pan MH, Wu CY, Hsiao CD, Yeh YH, Duan S, Paulson JC, Hsieh SL. SIGLEC-3 (CD33) serves as an immune checkpoint receptor for HBV infection. J Clin Invest 2021;131:e141965. [PMID: 34060491 DOI: 10.1172/jci141965] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 04/14/2021] [Indexed: 12/12/2022] Open

Affiliation(s)

Tsung-Yu Tsai PhD Program for Translational Medicine, China Medical University and Academia Sinica, Taichung, Taiwan.,Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
Ming-Ting Huang Genomics Research Center, Academia Sinica, Taipei, Taiwan
Pei-Shan Sung Genomics Research Center, Academia Sinica, Taipei, Taiwan
Cheng-Yuan Peng Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
Mi-Hua Tao Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
Hwai-I Yang Genomics Research Center, Academia Sinica, Taipei, Taiwan
Wei-Chiao Chang Department of Clinical Pharmacy, Taipei Medical University, Taipei, Taiwan
An-Suei Yang Genomics Research Center, Academia Sinica, Taipei, Taiwan
Chung-Ming Yu Genomics Research Center, Academia Sinica, Taipei, Taiwan
Ya-Ping Lin Genomics Research Center, Academia Sinica, Taipei, Taiwan
Ching-Yu Bau Genomics Research Center, Academia Sinica, Taipei, Taiwan
Chih-Jen Huang Genomics Research Center, Academia Sinica, Taipei, Taiwan
Mei-Hung Pan Genomics Research Center, Academia Sinica, Taipei, Taiwan
Chung-Yi Wu Genomics Research Center, Academia Sinica, Taipei, Taiwan
Chwan-Deng Hsiao Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
Yi-Hung Yeh Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
Shiteng Duan Department of Molecular Medicine, Scripps Research, La Jolla, California, USA
James C Paulson Department of Molecular Medicine, Scripps Research, La Jolla, California, USA
Shie-Liang Hsieh Genomics Research Center, Academia Sinica, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.,Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan

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Stockdale AJ, Silungwe NM, Shawa IT, Kreuels B, Gordon MA, Geretti AM. Diagnostic performance evaluation of hepatitis B e antigen rapid diagnostic tests in Malawi. BMC Infect Dis 2021;21:487. [PMID: 34044776 PMCID: PMC8157469 DOI: 10.1186/s12879-021-06134-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 04/19/2021] [Indexed: 12/18/2022] Open

Abstract

Background

The World Health Organization (WHO) has targeted a reduction in viral hepatitis-related mortality by 65% and incidence by 90% by 2030, necessitating enhanced hepatitis B treatment and prevention programmes in low- and middle-income countries. Hepatitis B e antigen (HBeAg) status is used in the assessment of eligibility for antiviral treatment and for prevention of mother-to-child transmission (PMTCT). Accordingly, the WHO has classified HBeAg rapid diagnostic tests (RDTs) as essential medical devices.

Methods

We assessed the performance characteristics of three commercially available HBeAg RDTs (SD Bioline, Alere, South Africa; Creative Diagnostics, USA; and Biopanda Reagents, UK) in two hepatitis B surface antigen-positive cohorts in Blantyre, Malawi: participants of a community study (n = 100) and hospitalised patients with cirrhosis or hepatocellular carcinoma (n = 94). Two investigators, blinded to the reference test result, independently assessed each assay. We used an enzyme-linked immunoassay (Monolisa HBeAg, Bio-Rad, France) as a reference test and quantified HBeAg concentration using dilutions of the WHO HBeAg standard. We related the findings to HBV DNA levels, and evaluated treatment eligibility using the TREAT-B score.

Results

Among 194 HBsAg positive patients, median age was 37 years, 42% were femaleand 26% were HIV co-infected. HBeAg prevalence was 47/194 (24%). The three RDTs showed diagnostic sensitivity of 28% (95% CI 16–43), 53% (38–68) and 72% (57–84) and specificity of 96–100% for detection of HBeAg. Overall inter-rater agreement κ statistic was high at 0.9–1.0. Sensitivity for identifying patients at the threshold where antiviral treatment is recommended for PMTCT, with HBV DNA > 200,000 IU/ml (39/194; 20%), was 22, 49 and 54% respectively. Using the RDTs in place of the reference HBeAg assay resulted in 3/43 (9%), 5/43 (12%) and 8/43 (19%) of patients meeting the TREAT-B treatment criteria being misclassified as ineligible for treatment. A relationship between HBeAg concentration and HBeAg detection by RDT was observed. A minimum HBeAg concentration of 2.2–3.1 log₁₀IU/ml was required to yield a reactive RDT.

Conclusions

Commercially available HBeAg RDTs lack sufficient sensitivity to accurately classify hepatitis B patients in Malawi. This has implications for hepatitis B public health programs in sub-Saharan Africa. Alternative diagnostic assays are recommended.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12879-021-06134-3.

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Luo X, Zhang R, Lu M, Liu S, Baba HA, Gerken G, Wedemeyer H, Broering R. Hippo Pathway Counter-Regulates Innate Immunity in Hepatitis B Virus Infection. Front Immunol 2021;12:684424. [PMID: 34113355 PMCID: PMC8185339 DOI: 10.3389/fimmu.2021.684424] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 05/11/2021] [Indexed: 01/17/2023] Open

Abstract

Whether hepatitis B virus (HBV) activates or represses innate immunity continues to be debated. Toll-like receptor (TLR) 2 has been identified to recognize HBV particles in human hepatocytes. The Hippo pathway, known for growth control, is suggested to play a vital role in immune regulation. Here, molecular interactions between HBV-triggered TLR signaling and the Hippo pathway were comprehensively investigated. Reanalysis of GSE69590 data, in which human hepatocytes have been treated with cell culture-derived HBV particles, identified changes in Hippo and NF-κB signaling. Immunocytochemical staining and western blotting revealed time-dependent nuclear translocation of YAP and NF-κB in HBV-exposed primary human and murine hepatocytes (PMH). Analysis of PMH isolated from MyD88- or IRAK4-deficient mice and the inhibition of TLR2 and MST1/2 in vitro confirmed the relation between TLR2 and Hippo signaling in HBV-induced immunity. Loss and gain of function experiments implied that Hippo-downstream effector YAP directly regulated IκBα expression. Functional investigations confirmed the regulation of Nfkbia promoter activity by the YAP/TEAD4 transcription factor complex. Administration of TLR ligands to mice highlighted the relevance of the TLR2-MyD88-IRAK4-Hippo axis in hepatic immunity. Interestingly, reanalysis of gene expression pattern in liver biopsies of patients chronically infected with HBV (GSE83148, GSE65359) indicated an activation of TLR2 and however, an MST1-dominated Hippo control in the immune clearance phase of patients with chronic HBV infection. We demonstrated that MyD88-dependent TLR signaling activates NF-κB and Hippo signaling, with YAP prompting the IκBα-mediated negative feedback, alongside NF-κB. Imbalance between immune induction and Hippo activation may have implications for the safety of novel HBV cure strategies interfering with pathogen recognition receptors.

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