Inhibition of HBsAg secretion by nucleic acid polymers in HepG2.2.15 cells

Blanchet, Matthieu; Sinnathamby, Vigigah; Vaillant, Andrew; Labonté, Patrick

doi:10.1016/j.antiviral.2019.02.009

Cited by 54 publications

(78 citation statements)

References 51 publications

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“…New approaches to treating HBV include an interference with SVP trafficking and secretion (Mohebbi et al, ). Candidate compounds include nucleic acid polymers (NAPs), cell‐permeable phosphorothioate oligonucleotides that had been shown to selectively inhibit SVP assembly/release in vitro and in vivo (Blanchet, Sinnathamby, Vaillant, & Labonte, ). Because NAPs can clear SVPs from the blood without any discernible direct interaction with HBV components, they are thought to target host proteins selectively involved in viral envelope trafficking (Beilstein, Blanchet, Vaillant, & Sureau, ).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B subviral envelope particles use the COPII machinery for intracellular transport via selective exploitation of Sec24A and Sec23B

Zeyen

Döring

Stieler

et al. 2020

Cellular Microbiology

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Hepatitis B virus (HBV) is a leading cause of liver disease. Its success as a human pathogen is related to the immense production of subviral envelope particles (SVPs) contributing to viral persistence by interfering with immune functions. To explore cellular pathways involved in SVP formation and egress, we investigated hostpathogen interactions. Yeast-based proteomics revealed Sec24A, a component of the coat protein complex II (COPII), as an interaction partner of the HBV envelope S domain. To understand how HBV co-opts COPII as a proviral machinery, we studied roles of key Sec proteins in HBV-expressing liver cells. Silencing of Sar1, Sec23, and Sec24, which promote COPII assembly concomitant with cargo loading, strongly diminished endoplasmic reticulum (ER) envelope export and SVP secretion. By analysing Sec paralog specificities, we unexpectedly found that the HBV envelope is a selective interaction partner of Sec24A and Sec23B whose functions could not be substituted by their related isoforms. In support, we found that HBV replication upregulated Sec24A and Sec23B transcription. Furthermore, HBV encountered the Sec24A/Sec23B complex via an interaction that involved the N-terminal half of Sec24A and a di-arginine motif of its S domain, mirroring a novel ER export code.Accordingly, an interference with the COPII/HBV cross-talk might display a tool to effectively inhibit SVP release.

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Section: Discussionmentioning

confidence: 99%

Hepatitis B subviral envelope particles use the COPII machinery for intracellular transport via selective exploitation of Sec24A and Sec23B

Zeyen

Döring

Stieler

et al. 2020

Cellular Microbiology

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“…Additionally, we previously showed 13 that under pegIFN it is not feasible to estimate HBsAg turnover because decreases in HBsAg occurred only during the second phase decrease of HDV RNA, which corresponds to cell death/loss. In contrast, REP 2139-Ca targets HBsAg SVP assembly and secretion 17 , which is the source of almost all circulating HBsAg, allowing for a direct assessment of HBsAg turnover. The estimated half-life of HBsAg (1.3 days) under REP 2139-Ca is strikingly short compared to the half-life of 38 days estimated under lamivudine 18 and approximately 7-fold shorter than estimated with deuterated HBsAg 19 suggesting that the turnover of HBV SVP may be more rapid in these patients than estimated in previous studies.…”

Section: Discussionmentioning

confidence: 99%

Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg

Shekhtman

Cotler

Hershkovich

et al. 2020

Sci Rep

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Hepatitis D virus (HDV) requires hepatitis B surface antigen (HBsAg) for its assembly and release. Current HBV treatments are only marginally effective against HDV because they fail to inhibit HBsAg production/secretion. However, monotherapy with the nucleic acid polymer REP 2139-Ca is accompanied by rapid declines in both HBsAg and HDV RNA. We used mathematical modeling to estimate HDV-HBsAg-host parameters and to elucidate the mode of action and efficacy of REP 2139-Ca against HDV in 12 treatment-naive HBV/HDV co-infected patients. The model accurately reproduced the observed decline of HBsAg and HDV, which was simultaneous. Median serum HBsAg half-life (t 1/2) was estimated as 1.3 [0.9-1.8] days corresponding to a pretreatment production and clearance of ~10 8 [10 7.7-10 8.3 ] IU/day. The HDV-infected cell loss was estimated to be 0.052 [0.035-0.074] days −1 corresponding to an infected cell t 1/2 = 13.3 days. The efficacy of blocking HBsAg and HDV production were 98.2 [94.5-99.9]% and 99.7 [96.0-99.8]%, respectively. In conclusion, both HBsAg production and HDV replication are effectively inhibited by REP 2139-Ca. Modeling HBsAg kinetics during REP 2139-Ca monotherapy indicates a short HBsAg half-life (1.3 days) suggesting a rapid turnover of HBsAg in HBV/ HDV co-infection. Chronic hepatitis B virus (HBV) and hepatitis D virus (HDV) co-infection affects an estimated 15-40 million persons worldwide 1,2 and is the most aggressive form of viral hepatitis 3. Therapy with pegylated interferon-α2a (pegIFN) is suboptimal in controlling HDV infection 4,5 and no other therapies are approved for the treatment of HDV. HDV requires hepatitis B surface antigen (HBsAg) for assembly and release. While the large isoform (L-HBsAg) is not requisite for HDV assembly and release, it is necessary for infectivity 6. Drugs that directly target HDV and reduce HDV levels are in development 7 , however the only anti-HBV treatment that affects HBsAg production is the nucleic acid polymer (NAP) REP 2139-Ca, which is accompanied by declines in both HBsAg and HDV RNA 8-11. Therefore, analyzing antiviral response during REP 2139-Ca monotherapy provides a unique opportunity to examine HBsAg production and clearance rates in HBV/HDV co-infected patients and to obtain a deeper understanding of REP 2139-Ca mode of action and efficacy against HDV. The aim of this study was to analyze the kinetics of HBV DNA, HBsAg, ALT and HDV RNA during REP 2139-Ca monotherapy and investigate the dynamics of HDV RNA and HBsAg using mathematical modelling.

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“…13 In in vitro studies, suppression of intracellular HBsAg and inhibition of HBsAg release by REP 2139 was not accompanied by any toxic effects. 8 In preclinical studies in cynomolgus monkeys, REP 2139 was not accompanied by alteration in liver function or histopathology, even at doses 10 times those used in the clinic. 10 Moreover in vivo, HBsAg declines were not associated with any detectable changes in liver function.…”

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confidence: 99%

“…7 The nucleic acid polymer (NAP) REP 2139 blocks the assembly of subviral particles (SVPs) in hepatocytes harboring covalently closed circular DNA or integrated HBV DNA via an as-yet unidentified host target. 8,9 This effect blocks the release of HBsAg and lowers intracellular HBsAg. 8 REP 2139 treatment in vivo in DHBV-infected ducks is accompanied by reduction in viral replication in the liver within 2 weeks, 10 rapid clearance of serum HBsAg with delayed clearance of serum HBV DNA, and control of infection in the liver (elimination of HBsAg and multilog reductions in HBV DNA and covalently closed circular DNA) maintained after the removal of therapy.…”

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confidence: 99%

“…8,9 This effect blocks the release of HBsAg and lowers intracellular HBsAg. 8 REP 2139 treatment in vivo in DHBV-infected ducks is accompanied by reduction in viral replication in the liver within 2 weeks, 10 rapid clearance of serum HBsAg with delayed clearance of serum HBV DNA, and control of infection in the liver (elimination of HBsAg and multilog reductions in HBV DNA and covalently closed circular DNA) maintained after the removal of therapy. 11 Monotherapy with the REP 2139 precursor REP 2055 10,12 in HB e antigen (HBeAg)-positive HBV chronic HBV infection was accompanied by HBsAg reduction, HBsAg and HBeAg seroconversion, and HBV DNA clearance; however, long-term virologic control similar to inactive chronic HBV (HBV DNA < 2000 IU/mL, normal alanine aminotransferase [ALT]) occurred in only 3 of 8 participants, persisting to 5 years in 2 of 8 participants with one of these participants additionally experiencing functional cure (HBV DNA target not detected [TND], HBsAg < lower limit of quantification [LLOQ], normal ALT).…”

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Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naïve to Nucleos(t)ide Therapy

Bazinet¹,

et al. 2020

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BACKGROUND & AIMS: Nucleic acid polymers (NAPs) inhibit assembly and secretion of hepatitis B virus (HBV) subviral particles. We performed an open-label, phase 2 study of the safety and efficacy of the NAPs REP 2139 or REP 2165 combined with tenofovir disoproxil fumarate (TDF) and pegylated interferon alfa-2a (pegIFN) in patients with chronic HBV infection who were negative for hepatitis B e antigen. METHODS: Following 24 weeks TDF therapy, 40 patients were randomly assigned to groups that received 48 weeks of experimental therapy (TDF þ pegIFN þ REP 2139-Mg or REP 2165-Mg) or 24 weeks of control therapy (TDF þ pegIFN) followed by 48 weeks of experimental therapy. Patients were then followed for a treatment-free period of 48 weeks. Primary outcomes were the safety and tolerability of REP 2139-Mg or REP 2165-Mg in combination with TDF þ pegIFN compared with TDF þ pegIFN alone through the first 48 weeks of therapy and subsequently throughout 48 weeks of NAP-based combination therapy (treatment weeks 24-72 in the experimental group and weeks 48-96 in the control group). Secondary outcomes were reductions in hepatitis B surface antigen (HBsAg) in control and experimental groups over the first 48 weeks of the study and throughout 48 weeks of combination therapy and virologic control (HBsAg positive, HBV DNA below 2000 IU/mL, normal level of alanine aminotransferase) or functional cure (HBsAg below 0.05 IU/mL, HBV DNA target not detected, normal level of alanine aminotransferase) after removal of all therapy. RESULTS: Levels of HBsAg, anti-HBs, and HBV DNA did not differ significantly between the groups given REP 2139 vs REP 2165. PegIFN-induced thrombocytopenia (P ¼ .299 vs controls) and neutropenia (P ¼ .112 vs controls) were unaffected by NAPs (REP 2139 vs REP 2165). Increases in levels of transaminases were significantly more frequent (P < .001 vs controls) and greater (P ¼ .002 vs controls) in the NAP groups (but did not produce symptoms), correlated with initial decrease in HBsAg, and normalized during therapy and follow-up. During the first 24 weeks of TDF and pegIFN administration, significantly higher proportions of

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Inhibition of HBsAg secretion by nucleic acid polymers in HepG2.2.15 cells

Cited by 54 publications

References 51 publications

Hepatitis B subviral envelope particles use the COPII machinery for intracellular transport via selective exploitation of Sec24A and Sec23B

Hepatitis B subviral envelope particles use the COPII machinery for intracellular transport via selective exploitation of Sec24A and Sec23B

Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg

Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naïve to Nucleos(t)ide Therapy

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Inhibition of HBsAg secretion by nucleic acid polymers in HepG2.2.15 cells

Cited by 54 publications

References 51 publications

Hepatitis B subviral envelope particles use the COPII machinery for intracellular transport via selective exploitation of Sec24A and Sec23B

Hepatitis B subviral envelope particles use the COPII machinery for intracellular transport via selective exploitation of Sec24A and Sec23B

Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg

Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naïve to Nucleos(t)ide Therapy

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Inhibition of HBsAg secretion by nucleic acid polymers in HepG2.2.15 cells