Class A capsid assembly modulator apoptotic elimination of hepatocytes with high HBV core antigen level in vivo is dependent on de novo core protein translation
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PROVIDER: PRJNA1033639 | ENA |
REPOSITORIES: ENA
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Project description:Treatment with hepatitis B virus (HBV) capsid assembly modulators that induce the formation of aberrant HBV core protein structures (CAM-A) leads to programmed cell death, apoptosis, of HBV-infected hepatocytes and subsequent reduction of HBV antigens, which differentiates CAM-A from other CAMs. The effect is dependent on the de novo synthesis and high levels of core protein.
2024-01-23 | GSE246563 | GEO
Project description:Capsid assembly is critical in the hepatitis B virus (HBV) life cycle, mediated by the viral core protein. Capsid assembly is the target for new anti-viral therapeutics known as capsid assembly modulators (CAMs) of which the CAM-aberrant (CAM-A) class induces aberrant shaped core protein structures and leads to hepatocyte cell death. This study aimed to identify the mechanism of action of CAM-A modulators leading to HBV-infected hepatocyte elimination where CAM-A-mediated hepatitis B surface antigen (HBsAg) reduction was evaluated in a stable HBV replicating cell line and in AAV-HBV-transduced C57BL/6, C57BL/6 SCID, and HBV-infected chimeric mice with humanized livers. Results showed that in vivo treatment with CAM-A modulators induced pronounced reductions in hepatitis B e antigen (HBeAg) and HBsAg, associated with a transient alanine amino transferase (ALT) increase. Both HBsAg and HBeAg reductions and ALT increase were delayed in C57BL/6 SCID and chimeric mice, suggesting that adaptive immune responses may indirectly contribute. However, CD8+ T cell depletion in transduced wild-type mice did not impact antigen reduction, indicating that CD8+ T cell responses are not essential. Transient ALT elevation in AAV-HBV-transduced mice coincided with a transient increase in endoplasmic reticulum stress and apoptosis markers, followed by detection of a proliferation marker. Microarray data revealed antigen presentation pathway (major histocompatibility complex class I molecules) upregulation, overlapping with the apoptosis. Combination treatment with HBV-specific siRNA demonstrated that CAM-A-mediated HBsAg reduction is dependent on de novo core protein translation. To conclude, CAM-A treatment eradicates HBV-infected hepatocytes with high core protein levels through the induction of apoptosis, which can be a promising approach as part of a regimen to achieve functional cure.ImportanceTreatment with hepatitis B virus (HBV) capsid assembly modulators that induce the formation of aberrant HBV core protein structures (CAM-A) leads to programmed cell death, apoptosis, of HBV-infected hepatocytes and subsequent reduction of HBV antigens, which differentiates CAM-A from other CAMs. The effect is dependent on the de novo synthesis and high levels of core protein.
| S-EPMC10949496 | biostudies-literature
Project description:Several classes of capsid assembly modulators (CAMs) are currently being developed for chronic hepatitis B (CHB) cure. Both class A (CAM-A) and class E (CAM-E) CAMs disrupt nucleocapsid assembly and reduce extracellular hepatitis B virus (HBV) DNA. However, only CAM-As have been shown to reduce the number of HBV-infected cells in the animal models. However, there has been limited efficacy to date of CAM-A molecules achieving this secondary mechanism of HBV-infected cell clearance in CHB clinical trials. To investigate this disconnect, we performed comparative experiments with tool compounds from each class to further explore these unique features and antiviral activity of CAM-A across HBV-infected primary human hepatocytes (PHH), as well as in two different HBV mouse models (immunodeficient mice repopulated with human hepatocytes and AAV-HBV). Mechanistic studies in HBV-infected PHH revealed that CAM-A, but not CAM-E, induced dose-dependent aggregation of HBV core protein (HBc) in the nucleus. Experiments with siRNA, resulted in identification of the ubiquitin-binding protein p62 as a factor negatively regulating the size of these aggregates. Furthermore, we found that only the CAM-A is able to induce HBc-positive cell death in vivo with the loss of HBV-infected cells positively correlated to the levels of intrahepatic HBc. Profiling of intrahepatic HBc levels across CHB patient liver biopsies demonstrated a significantly lower level of HBc per hepatocyte than either of the HBV mouse models. Taken together, these data demonstrate that CAMs of class A have a unique secondary mechanism that has potential to specifically affect viability of HBV-infected hepatocytes. At the same time, the clearance of infected hepatocytes may depend on the level of HBc expression thereby limiting the therapeutic potential for this class of molecules.
2024-05-21 | GSE260966 | GEO
Project description:Selective depletion of HBV-infected hepatocytes by class A capsid assembly modulators require high levels of intrahepatic HBV core protein
| PRJNA1084747 | ENA
Project description:Canocapavir is a novel antiviral agent with characteristics of core protein allosteric modulators (CpAMs) that is currently in a phase II clinical trial for treatment of hepatitis B virus (HBV) infection. Herein, we show that Canocapavir prevented the encapsidation of HBV pregenomic RNA and increased the accumulation of cytoplasmic empty capsids, presumably by targeting the hydrophobic pocket at the dimer-dimer interface of HBV core protein (HBc). Canocapavir treatment markedly reduced the egress of naked capsids, which could be reversed by Alix overexpression through a mechanism other than direct association of Alix with HBc. Moreover, Canocapavir interfered with the interaction between HBc and HBV large surface protein, resulting in diminished production of empty virions. Of particular note, Canocapavir induced a conformational change of capsids, with the C-terminus of HBc linker region fully exposed on the exterior of capsids. We posit that the allosteric effect may have great importance in the anti-HBV activity of Canocapavir, given the emerging virological significance of HBc linker region. In support of this notion, the mutation at HBc V124W typically recapitulated the conformational change of the empty capsid with aberrant cytoplasmic accumulation. Collectively, our results indicate Canocapavir as a mechanistically distinct type of CpAMs against HBV infection.
| S-EPMC10223407 | biostudies-literature
Project description:Capsid assembly modulators (CpAMs) represent a new class of antivirals targeting hepatitis B virus (HBV) core protein to disrupt the assembly process. In this work, a novel chemotype featuring a fused heterocycle amide was discovered through pharmacophore exploration. Lead optimization resulted in compound 8 with an EC50 value of 511 nM, and then methyl substitution on the piperazine was found to improve the in vitro potency remarkably. Further SAR studies established the key compound SHR5133, which showed high in vitro antiviral potency, favorable pharmacokinetic profiles across species, and robust in vivo efficacy.
| S-EPMC8919393 | biostudies-literature
Project description:Brief assessment of VEEV TC-83 Capsid:RNA interactions.
2020-05-25 | GSE132125 | GEO
Project description:Organisms invest significant effort into maintaining genome stability. However, in diverse groups of eukaryotes, portions or entire chromosomes are lost in early development or during sex determination, a process known as programmed DNA elimination. Little is known about how different segments of the genome are reproducibly retained and discarded during programmed DNA elimination. We tested the hypothesis that selective retention is mediated by regulation of centromere-mediated association of chromosome segments with the mitotic spindle. We report that on the holocentric chromosomes of the nematode Ascaris, the core centromeric histone CENP-A is localized differently in cells undergoing DNA elimination from those undergoing germline mitosis. Prior to DNA elimination, CENP-A is significantly reduced in chromosome regions that will be lost. CENP-A reduction in eliminated genomic regions leads to the absence of kinetochores and microtubule attachment sites necessary for chromosome segregation, and thus the loss of these DNA regions during Ascaris programmed DNA elimination. Our results show that holocentric chromosome organization in Ascaris is regulated and that changes in CENP-A deposition specify which portions of chromosomes will be eliminated during programmed DNA elimination. A total of 62 samples are analyzed. These include: (1). CENP-A ChIP-seq on 12 developmental stages with input and replicates (12 x 2 x 2 samples); (2). CENP-C ChIP-seq on 3 developmental stages with input and replicates (total 8 samples); and (3). Histone marks ChIP-seq with 6 samples
2016-07-15 | E-GEOD-76914 | biostudies-arrayexpress
Project description:BackgroundGLS4 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator (class I) that can inhibit HBV replication by interfering with the assembly and disassembly of HBV nucleocapsid. Here, we evaluated its antiviral activity, pharmacokinetics, and tolerability in a double-blind, randomized, parallel, entecavir-controlled study.MethodsTwenty-four patients with chronic HBV were randomized to receive a 28-day course of GLS4 (120 or 240 mg) and ritonavir (100 mg) combination (cohorts A and B, respectively) or entecavir treatment (cohort C) at a 1:1:1 ratio. Patients were followed up for 40 days in a phase 1b study.ResultsThe GLS4/ritonavir combination was a tolerated combination for the treatment of chronic HBV infection. A total of 2, 3, and 3 subjects presented with alanine aminotransferase flare in cohorts A, B, and C, respectively. This contributed to the withdrawal of 1, 2, and 1 patient from cohorts A, B, and C, respectively. The mean Ctrough of GLS4 was 205-218 ng/mL, which was approximately 3.7-3.9 times the 90% effective concentration (55.8 ng/mL), with a lower accumulation (accumulation rate, 1.1-2.0). In cohorts A, B, and C, the mean declines in HBV DNA after 28 days of treatment were -1.42, -2.13, and -3.5 log10 IU/mL; in hepatitis B surface antigen were -0.06, -0.14, and -0.33 log10 IU/mL; in pregenomic RNA were -0.75, -1.78, and -0.96 log10 copies/mL; and in hepatitis B core antigen were -0.23, -0.5, and -0.44 log10 U/mL, respectively.ConclusionsTreatment with 120 mg GLS4 was tolerated and had antiviral activity in patients with chronic HBV infection.Clinical trials registrationChinese Clinical Trial Registry; CTR20160068. http://www.chinadrugtrials.org.cn.
| S-EPMC8516514 | biostudies-literature
Project description:ATACseq analysis of chromatin accessibility in Huh7 cells upon YFV capsid expression
2020-11-15 | GSE152623 | GEO