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Article ; Online: Hepatitis B core-specific memory B cell responses associate with clinical parameters in patients with chronic HBV.

Vanwolleghem, Thomas / Groothuismink, Zwier M A / Kreefft, Kim / Hung, Magdeleine / Novikov, Nikolai / Boonstra, Andre

2020 Volume 73, Issue 1, Page(s) 52–61

Abstract: Background & aims: Little is known about the frequency, phenotype and function of HBV-specific B cells during chronic infection. Here we study HBcAg and HBsAg-specific B cells in different clinical phases of a chronic HBV infection.: Methods: We ... ...

Abstract	Background & aims: Little is known about the frequency, phenotype and function of HBV-specific B cells during chronic infection. Here we study HBcAg and HBsAg-specific B cells in different clinical phases of a chronic HBV infection. Methods: We included 118 treatment naïve and 34 nucleos(t)ide analogue-treated patients with chronic HBV and 23 healthy HBsAg-vaccinated controls. Global and HBV-specific B lymphocytes were examined by FACS using fluorescently labeled HBsAg and HBcAg as baits. Functional HBV-specific B cell responses were quantified in B cell ELISPOT assays. Anti-HBs and anti-HBc antibodies were measured in serum and in ELISPOT supernatant by ELISA. Results: Higher HBcAg-directed B cell responses were found in HBV clinical phases with elevated vs. low serum alanine aminotransferase (ALT) levels, irrespective of the HBeAg-status. In contrast, HBsAg-directed responses were lower and did not significantly fluctuate. In individual patients a mean 17.8-fold more circulating B cells target HBcAg than HBsAg baits. These HBcAg-specific B cells present a classical memory B cell profile and have slightly higher CD69 expression levels compared to global memory B cells. Viral suppression and ALT normalization upon treatment led to a numeric and functional reduction of HBcAg-specific B cell responses, accompanied by progressive decreases in serum anti-HBc antibodies. Conclusion: HBcAg-specific memory B cells present a classical memory B cell phenotype, vary in number and function throughout HBV's natural history and are significantly reduced during antiviral treatment. Lay summary: In recent years, studies examining the role of B cells during chronic hepatitis B virus infection have regained interest. We show that circulating B cells more often target the hepatitis B core antigen than the hepatitis surface antigen. Moreover, these hepatitis B core-specific B cells associate with the natural history of chronic HBV, and their responses decline during effective antiviral treatment.
MeSH term(s)	Adult ; Antibody Formation/drug effects ; Antibody Formation/immunology ; Antiviral Agents/pharmacology ; B-Lymphocyte Subsets/classification ; B-Lymphocyte Subsets/drug effects ; B-Lymphocyte Subsets/virology ; Female ; Hepatitis B Core Antigens/immunology ; Hepatitis B Surface Antigens/immunology ; Hepatitis B virus/genetics ; Hepatitis B virus/immunology ; Hepatitis B, Chronic/blood ; Hepatitis B, Chronic/drug therapy ; Hepatitis B, Chronic/immunology ; Hepatitis B, Chronic/virology ; Humans ; Immunologic Memory/drug effects ; Immunologic Memory/immunology ; Male
Chemical Substances	Antiviral Agents ; Hepatitis B Core Antigens ; Hepatitis B Surface Antigens
Language	English
Publishing date	2020-02-13
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2020.01.024
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Article ; Online: Elucidating molecular interactions of

Hung, Magdeleine / Tokarsky, E John / Lagpacan, Leanna / Zhang, Lijun / Suo, Zucai / Lansdon, Eric B

Communications biology

2019 Volume 2, Page(s) 469

Abstract: Emtricitabine (FTC) and lamivudine (3TC), containing an oxathiolane ring with unnatural (-)-stereochemistry, are widely used nucleoside reverse transcriptase inhibitors (NRTIs) in anti-HIV therapy. Treatment with FTC or 3TC primarily selects for the HIV- ... ...

Abstract	Emtricitabine (FTC) and lamivudine (3TC), containing an oxathiolane ring with unnatural (-)-stereochemistry, are widely used nucleoside reverse transcriptase inhibitors (NRTIs) in anti-HIV therapy. Treatment with FTC or 3TC primarily selects for the HIV-1 RT M184V/I resistance mutations. Here we provide a comprehensive kinetic and structural basis for inhibiting HIV-1 RT by (-)-FTC-TP and (-)-3TC-TP and drug resistance by M184V. (-)-FTC-TP and (-)-3TC-TP have higher binding affinities (1/
MeSH term(s)	Alleles ; Amino Acid Substitution ; Databases, Genetic ; Drug Resistance, Viral ; HIV Infections/drug therapy ; HIV Infections/virology ; HIV Reverse Transcriptase/antagonists & inhibitors ; HIV Reverse Transcriptase/chemistry ; HIV Reverse Transcriptase/genetics ; HIV-1/drug effects ; HIV-1/enzymology ; HIV-1/genetics ; Humans ; Microbial Sensitivity Tests ; Mutation ; Nucleotides/chemistry ; Nucleotides/pharmacology ; Reverse Transcriptase Inhibitors/chemistry ; Reverse Transcriptase Inhibitors/pharmacology
Chemical Substances	Nucleotides ; Reverse Transcriptase Inhibitors ; reverse transcriptase, Human immunodeficiency virus 1 (EC 2.7.7.-) ; HIV Reverse Transcriptase (EC 2.7.7.49)
Language	English
Publishing date	2019-12-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-019-0706-x
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Article ; Online: HIV envelope antibodies and TLR7 agonist partially prevent viral rebound in chronically SHIV-infected monkeys.

Moldt, Brian / Chandrashekar, Abishek / Borducchi, Erica N / Nkolola, Joseph P / Stephenson, Heather / Nagel, Mark / Hung, Magdeleine / Goldsmith, Joshua / Pace, Craig S / Carr, Brian / Thomsen, Nathan D / Blair, Wade S / Geleziunas, Romas / Barouch, Dan H

PLoS pathogens

2022 Volume 18, Issue 4, Page(s) e1010467

Abstract: A key challenge for the development of a cure to HIV-1 infection is the persistent viral reservoir established during early infection. Previous studies using Toll-like receptor 7 (TLR7) agonists and broadly neutralizing antibodies (bNAbs) have shown ... ...

Abstract	A key challenge for the development of a cure to HIV-1 infection is the persistent viral reservoir established during early infection. Previous studies using Toll-like receptor 7 (TLR7) agonists and broadly neutralizing antibodies (bNAbs) have shown delay or prevention of viral rebound following antiretroviral therapy (ART) discontinuation in simian-human immunodeficiency virus (SHIV)-infected rhesus macaques. In these prior studies, ART was initiated early during acute infection, which limited the size and diversity of the viral reservoir. Here we evaluated in SHIV-infected rhesus macaques that did not initiate ART until 1 year into chronic infection whether the TLR7 agonist vesatolimod in combination with the bNAb PGT121, formatted either as a human IgG1, an effector enhanced IgG1, or an anti-CD3 bispecific antibody, would delay or prevent viral rebound following ART discontinuation. We found that all 3 antibody formats in combination with vesatolimod were able to prevent viral rebound following ART discontinuation in a subset of animals. These data indicate that a TLR7 agonist combined with antibodies may be a promising strategy to achieve long-term ART-free HIV remission in humans.
MeSH term(s)	Animals ; Anti-Retroviral Agents/pharmacology ; Anti-Retroviral Agents/therapeutic use ; Broadly Neutralizing Antibodies ; HIV Antibodies/therapeutic use ; HIV Infections ; HIV-1 ; Immunoglobulin G ; Macaca mulatta ; Simian Acquired Immunodeficiency Syndrome ; Simian Immunodeficiency Virus ; Toll-Like Receptor 7/agonists ; Viral Load
Chemical Substances	Anti-Retroviral Agents ; Broadly Neutralizing Antibodies ; HIV Antibodies ; Immunoglobulin G ; Toll-Like Receptor 7
Language	English
Publishing date	2022-04-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010467
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Article ; Online: Effects of small molecule-induced dimerization on the programmed death ligand 1 protein life cycle.

Chai, Ilean / Kornyeyev, Dmytro / Hsieh, Edward / Magombedze, Gesham / Stapleton, Lance / Hung, Magdeleine / Kwon, Hyock Joo / Stefanutti, Erin / Belzile, JeanPhilippe / Czerwieniec, Gregg / Wang, Adele Y / Morar, Mariya / Lad, Latesh

Scientific reports

2022 Volume 12, Issue 1, Page(s) 21286

Abstract: The programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) checkpoint blockade is central to Immuno-Oncology based therapies, and alternatives to antibody blockers of this interaction are an active area of research due to antibody related toxicities. ...

Abstract	The programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) checkpoint blockade is central to Immuno-Oncology based therapies, and alternatives to antibody blockers of this interaction are an active area of research due to antibody related toxicities. Recently, small molecule compounds that induce PD-L1 dimerization and occlusion of PD-1 binding site have been identified and developed for clinical trials. This mechanism invokes an oligomeric state of PD-L1 not observed in cells previously, as PD-L1 is generally believed to function as a monomer. Therefore, understanding the cellular lifecycle of the induced PD-L1 dimer is of keen interest. Our report describes a moderate but consistent increase in the PD-L1 rate of degradation observed upon protein dimerization as compared to the monomer counterpart. This subtle change, while not resolved by measuring total PD-L1 cellular levels by western blotting, triggered investigations of the overall protein distribution across various cellular compartments. We show that PD-L1 dimerization does not lead to rapid internalization of neither transfected nor endogenously expressed protein forms. Instead, evidence is presented that dimerization results in retention of PD-L1 intracellularly, which concomitantly correlates with its reduction on the cell surface. Therefore, the obtained data for the first time points to the ability of small molecules to induce dimerization of the newly synthesized PD-L1 in addition to the protein already present on the plasma membrane. Overall, this work serves to improve our understanding of this important target on a molecular level in order to guide advances in drug development.
Language	English
Publishing date	2022-12-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-25417-6
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Article ; Online: Spatiotemporal Analysis of Hepatitis B Virus X Protein in Primary Human Hepatocytes.

Kornyeyev, Dmytro / Ramakrishnan, Dhivya / Voitenleitner, Christian / Livingston, Christine M / Xing, Weimei / Hung, Magdeleine / Kwon, Hyock Joo / Fletcher, Simon P / Beran, Rudolf K

Journal of virology

2019 Volume 93, Issue 16

Abstract: The structural maintenance of chromosomes 5/6 complex (Smc5/6) is a host restriction factor that suppresses hepatitis B virus (HBV) transcription. HBV counters this restriction by expressing the X protein (HBx), which redirects the host DNA damage- ... ...

Abstract	The structural maintenance of chromosomes 5/6 complex (Smc5/6) is a host restriction factor that suppresses hepatitis B virus (HBV) transcription. HBV counters this restriction by expressing the X protein (HBx), which redirects the host DNA damage-binding protein 1 (DDB1) E3 ubiquitin ligase to target Smc5/6 for degradation. HBx is an attractive therapeutic target for the treatment of chronic hepatitis B (CHB), but it is challenging to study this important viral protein in the context of natural infection due to the lack of a highly specific and sensitive HBx antibody. In this study, we developed a novel monoclonal antibody that enables detection of HBx protein in HBV-infected primary human hepatocytes (PHH) by Western blotting and immunofluorescence. Confocal imaging studies with this antibody demonstrated that HBx is predominantly located in the nucleus of HBV-infected PHH, where it exhibits a diffuse staining pattern. In contrast, a DDB1-binding-deficient HBx mutant was detected in both the cytoplasm and nucleus, suggesting that the DDB1 interaction plays an important role in the nuclear localization of HBx. Our study also revealed that HBx is expressed early after infection and has a short half-life (∼3 h) in HBV-infected PHH. In addition, we found that treatment with small interfering RNAs (siRNAs) that target DDB1 or HBx mRNA decreased HBx protein levels and led to the reappearance of Smc6 in the nuclei of HBV-infected PHH. Collectively, these studies provide the first spatiotemporal analysis of HBx in a natural infection system and also suggest that HBV transcriptional silencing by Smc5/6 can be restored by therapeutic targeting of HBx.
MeSH term(s)	Amino Acid Sequence ; Antibodies, Monoclonal/immunology ; DNA-Binding Proteins/metabolism ; Enzyme-Linked Immunosorbent Assay ; Fluorescent Antibody Technique ; Gene Expression ; Gene Expression Regulation, Viral ; Hepatitis B/virology ; Hepatitis B virus/physiology ; Hepatocytes/virology ; Host-Pathogen Interactions ; Humans ; Peptides/chemistry ; Peptides/immunology ; Peptides/metabolism ; Protein Binding ; Protein Transport ; Trans-Activators/chemistry ; Trans-Activators/genetics ; Trans-Activators/immunology ; Trans-Activators/metabolism
Chemical Substances	Antibodies, Monoclonal ; DDB1 protein, human ; DNA-Binding Proteins ; Peptides ; Trans-Activators ; hepatitis B virus X protein
Language	English
Publishing date	2019-07-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00248-19
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Zs.A 609: Show issues

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Article ; Online: Preparation of HCV NS3 and NS5B proteins to support small-molecule drug discovery.

Hung, Magdeleine / Wang, Ruth / Liu, Xiaohong

Current protocols in pharmacology

2011 Volume Chapter 13, Page(s) Unit13B.6

Abstract: Production of high-quality, well-characterized recombinant proteins facilitates screening of compound libraries. The protocols detailed in this unit are used to purify three recombinant enzymes that are widely used in HCV research: the HCV NS3 protease ... ...

Abstract	Production of high-quality, well-characterized recombinant proteins facilitates screening of compound libraries. The protocols detailed in this unit are used to purify three recombinant enzymes that are widely used in HCV research: the HCV NS3 protease domain, the helicase domain as an NS3+NS4A complex, and the NS5B RNA-dependent RNA polymerase. The active enzymes are purified to homogeneity by two-column chromatography to support a screening program for HCV inhibitors.
MeSH term(s)	Drug Evaluation, Preclinical/methods ; Enzyme Inhibitors/pharmacology ; Hepacivirus/drug effects ; Hepacivirus/enzymology ; In Vitro Techniques ; Recombinant Proteins/antagonists & inhibitors ; Recombinant Proteins/chemistry ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry
Chemical Substances	Enzyme Inhibitors ; Recombinant Proteins ; Viral Nonstructural Proteins
Language	English
Publishing date	2011-09
Publishing country	United States
Document type	Journal Article
ISSN	1934-8290
ISSN (online)	1934-8290
DOI	10.1002/0471141755.ph13b06s54
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Article ; Online: Comparative characterization of B cells specific for HBV nucleocapsid and envelope proteins in patients with chronic hepatitis B.

Le Bert, Nina / Salimzadeh, Loghman / Gill, Upkar Singh / Dutertre, Charles-Antoine / Facchetti, Floriana / Tan, Anthony / Hung, Magdeleine / Novikov, Nikolai / Lampertico, Pietro / Fletcher, Simon Paul / Kennedy, Patrick Thomas Francis / Bertoletti, Antonio

Journal of hepatology

2019 Volume 72, Issue 1, Page(s) 34–44

Abstract: Background & aims: Knowledge about the regulation of anti-HBV humoral immunity during natural HBV infection is limited. We recently utilized dual fluorochrome-conjugated HBsAg to demonstrate, in patients with chronic HBV (CHB) infection, the functional ... ...

Abstract	Background & aims: Knowledge about the regulation of anti-HBV humoral immunity during natural HBV infection is limited. We recently utilized dual fluorochrome-conjugated HBsAg to demonstrate, in patients with chronic HBV (CHB) infection, the functional impairment of their HBsAg-specific B cells. However, the features of their HBcAg-specific B cells are unknown. Here we developed a method to directly visualize, select and characterize HBcAg-specific B cells in parallel with HBsAg-specific B cells. Methods: Fluorochrome-conjugated HBcAg reagents were synthesized and utilized to directly detect ex vivo HBcAg-specific B cells in 36 patients with CHB. The frequency, phenotype, functional maturation and transcriptomic profile of HBcAg-specific B cells was studied by flow cytometry, in vitro maturation assays and NanoString-based detection of expression of immune genes, which we compared with HBsAg-specific B cells and total B cells. Results: HBcAg-specific B cells are present at a higher frequency than HBsAg-specific B cells in patients with CHB and, unlike HBsAg-specific B cells, they mature efficiently into antibody-secreting cells in vitro. Their phenotypic and transcriptomic profiles show that HBcAg-specific B cells are preferentially IgG+ memory B cells. However, despite their phenotypic and functional differences, HBcAg- and HBsAg-specific B cells from patients with CHB share an mRNA expression pattern that differs from global memory B cells and is characterized by high expression of genes indicative of cross-presentation and innate immune activity. Conclusions: During chronic HBV infection, a direct relation exists between serological detection of anti-HBs and anti-HBc antibodies, and the quantity and function of their respective specific B cells. However, the transcriptomic analysis performed in HBsAg- and HBcAg-specific B cells suggests additional roles of HBV-specific B cells beyond the production of antibodies. Lay summary: Protection of viral infection necessitates the production of antibodies that are generated by specialized cells of the immune system called B cells. During chronic HBV infection, antibodies against the internal part of the virus (core or HBcAg) are detectable while the antibodies directed against the virus envelope (surface or HBsAg) are not present. Here we developed a method that allows us to directly visualize ex vivo the B cells specific for these 2 viral components, highlighting their differences and similarities, and showing how 2 components of the same virus can have different impacts on the function of antiviral B cells.
MeSH term(s)	Adolescent ; Adult ; B-Lymphocytes/immunology ; Child ; Cohort Studies ; DNA, Viral/blood ; DNA, Viral/immunology ; Female ; Hepatitis B Antibodies/blood ; Hepatitis B Core Antigens/immunology ; Hepatitis B Surface Antigens/immunology ; Hepatitis B virus/immunology ; Hepatitis B, Chronic/blood ; Hepatitis B, Chronic/immunology ; Hepatitis B, Chronic/virology ; Humans ; Male ; Middle Aged ; Nucleocapsid Proteins/immunology ; Phenotype ; Transcriptome ; Viral Envelope Proteins/immunology ; Young Adult
Chemical Substances	DNA, Viral ; Hepatitis B Antibodies ; Hepatitis B Core Antigens ; Hepatitis B Surface Antigens ; Nucleocapsid Proteins ; Viral Envelope Proteins ; nucleocapsid protein, Hepatitis virus
Language	English
Publishing date	2019-07-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2019.07.015
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Article ; Online: PD-1 Blockade and TLR7 Activation Lack Therapeutic Benefit in Chronic Simian Immunodeficiency Virus-Infected Macaques on Antiretroviral Therapy.

Bekerman, Elena / Hesselgesser, Joseph / Carr, Brian / Nagel, Mark / Hung, Magdeleine / Wang, Adele / Stapleton, Lance / von Gegerfelt, Agneta / Elyard, Hanne Andersen / Lifson, Jeffrey D / Geleziunas, Romas

Antimicrobial agents and chemotherapy

2019 Volume 63, Issue 11

Abstract: Antiretroviral therapy (ART) limits human immunodeficiency virus 1 (HIV-1) replication but does not eliminate the long-lived reservoir established shortly after viral acquisition. A successful HIV cure intervention necessitates either elimination or ... ...

Abstract	Antiretroviral therapy (ART) limits human immunodeficiency virus 1 (HIV-1) replication but does not eliminate the long-lived reservoir established shortly after viral acquisition. A successful HIV cure intervention necessitates either elimination or generation of long-term immune control of the persistent viral reservoir. Immune modulating strategies in conjunction with ART hold promise for achieving cure by inducing viral antigen expression and augmenting infected cell killing. Programmed death-1 (PD-1) blockade is a potential means to both activate and eliminate the latent reservoir by restoring exhausted T cell function. We assessed the therapeutic efficacy of PD-1 blockade, Toll-like receptor 7 (TLR7) activation with the agonist vesatolimod, or a combination of the two agents in chronically simian immunodeficiency virus (SIV)-infected macaques suppressed with ART for more than 2 years. Despite achieving extended anti-PD-1 antibody plasma exposure and TLR7-dependent immune activation after multiple administrations, neither individual treatment nor the combination resulted in changes to viral rebound kinetics following ART interruption or reduction in the SIV reservoir size. Our data in the context of other reports demonstrating improved viral control upon PD-1 blockade suggest that its therapeutic utility may be restricted to specific experimental conditions or treatment times during viral pathogenesis.
MeSH term(s)	Animals ; Anti-Retroviral Agents/therapeutic use ; Antibodies/immunology ; Antiviral Agents/pharmacology ; Flow Cytometry ; Macaca mulatta ; Male ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/immunology ; Programmed Cell Death 1 Receptor/metabolism ; Pteridines/pharmacology ; Simian Acquired Immunodeficiency Syndrome/drug therapy ; Simian Immunodeficiency Virus/drug effects ; Toll-Like Receptor 7/metabolism ; Viral Load/drug effects
Chemical Substances	Anti-Retroviral Agents ; Antibodies ; Antiviral Agents ; Programmed Cell Death 1 Receptor ; Pteridines ; Toll-Like Receptor 7 ; vesatolimod (O8M467C50G)
Language	English
Publishing date	2019-10-22
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.01163-19
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Zs.A 809: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Einzelsignatur: Show issues

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Article ; Online: PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection.

Salimzadeh, Loghman / Le Bert, Nina / Dutertre, Charles-A / Gill, Upkar S / Newell, Evan W / Frey, Christian / Hung, Magdeleine / Novikov, Nikolai / Fletcher, Simon / Kennedy, Patrick Tf / Bertoletti, Antonio

The Journal of clinical investigation

2018 Volume 128, Issue 10, Page(s) 4573–4587

Abstract: Chronic HBV (CHB) infection suppresses virus-specific T cells, but its impact on humoral immunity has been poorly analyzed. Here, we developed a dual-staining method that utilizes hepatitis B virus (HBV) surface antigens (HBsAg) labeled with ... ...

Abstract	Chronic HBV (CHB) infection suppresses virus-specific T cells, but its impact on humoral immunity has been poorly analyzed. Here, we developed a dual-staining method that utilizes hepatitis B virus (HBV) surface antigens (HBsAg) labeled with fluorochromes as "baits" for specific ex vivo detection of HBsAg-specific B cells and analysis of their quantity, function, and phenotype. We studied healthy vaccinated subjects (n = 18) and patients with resolved (n = 21), acute (n = 11), or chronic (n = 96) HBV infection and observed that frequencies of circulating HBsAg-specific B cells were independent of HBV infection status. In contrast, the presence of serum HBsAg affected function and phenotype of HBsAg-specific B cells that were unable to mature in vitro into Ab-secreting cells and displayed an increased expression of markers linked to hyperactivation (CD21lo) and exhaustion (PD-1). Importantly, B cell alterations were not limited to HBsAg-specific B cells, but affected the global B cell population. HBsAg-specific B cell maturation could be partially restored by a method involving the combination of the cytokines IL-2 and IL-21 and CD40L-expressing feeder cells and was further boosted by the addition of anti-PD-1 Abs. In conclusion, HBV infection has a marked impact on global and HBV-specific humoral immunity, yet HBsAg-specific B cells are amenable to a partial rescue by B cell-maturing cytokines and PD-1 blockade.
MeSH term(s)	Adult ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; CD40 Ligand/immunology ; Female ; Hepatitis B Surface Antigens/immunology ; Hepatitis B, Chronic/immunology ; Hepatitis B, Chronic/pathology ; Hepatitis B, Chronic/therapy ; Humans ; Immunity, Humoral ; Interleukin-2/immunology ; Interleukins/immunology ; Male ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/immunology
Chemical Substances	Hepatitis B Surface Antigens ; IL2 protein, human ; Interleukin-2 ; Interleukins ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; CD40 Ligand (147205-72-9) ; interleukin-21 (MKM3CA6LT1)
Language	English
Publishing date	2018-08-07
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI121957
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Article ; Online: Development and application of a fast, reproducible assay to measure HCV NS3 protease activity using Escherichia coli lysate.

Han, Bin / Dvory-Sobol, Hadas / Greenstein, Andrew / McCarville, Joseph F / Hung, Magdeleine / Liu, Xiaohong / Miller, Michael D / Mo, Hongmei

Journal of virological methods

2015 Volume 225, Page(s) 76–86

Abstract: The hepatitis C virus (HCV) NS3/4A protease is a key target of efforts to develop direct-acting antiviral inhibitors for treatment of chronic HCV infection. In vitro analyses of the effects of NS3/4A mutations and polymorphisms on protease inhibitor (PI) ...

Abstract	The hepatitis C virus (HCV) NS3/4A protease is a key target of efforts to develop direct-acting antiviral inhibitors for treatment of chronic HCV infection. In vitro analyses of the effects of NS3/4A mutations and polymorphisms on protease inhibitor (PI) susceptibility are essential to nonclinical and clinical compound characterization, but can be hampered by time and technical limitations of current in vitro methods using replicon or purified protein systems. We have developed a fast and simple method utilizing full-length NS3/4A protease inducibly expressed in Escherichia coli cells. Minimally processed E. coli whole cell lysate was used for analyzing NS3/4A protease activity and inhibition by antiviral compounds. Assay conditions were optimized to develop a reproducible assay that can be used for efficient analysis of NS3 protease mutants with poor replication capacity in the replicon system. IC50 fold-changes for NS3 mutants relative to their wild-types generated by this NS3 assay are comparable to those observed in the replicon system, with an R(2) of 0.82 for the values obtained by the two methods. In addition, we demonstrate that this assay can be successfully used for population and clonal phenotyping of patient samples and characterization of PIs against the NS3/4A protease from HCV genotypes 1-6.
MeSH term(s)	Antiviral Agents/metabolism ; Escherichia coli/genetics ; Hepacivirus/enzymology ; Hepatitis C/virology ; Humans ; Inhibitory Concentration 50 ; Mutant Proteins/antagonists & inhibitors ; Mutant Proteins/genetics ; Mutant Proteins/metabolism ; Protease Inhibitors/metabolism ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Reproducibility of Results ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/isolation & purification ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Antiviral Agents ; Mutant Proteins ; NS3 protein, hepatitis C virus ; Protease Inhibitors ; Recombinant Proteins ; Viral Nonstructural Proteins
Language	English
Publishing date	2015-12-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	8013-5
ISSN	1879-0984 ; 0166-0934
ISSN (online)	1879-0984
ISSN	0166-0934
DOI	10.1016/j.jviromet.2015.09.002
Database	MEDical Literature Analysis and Retrieval System OnLINE

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