scholarly journals Molecular mechanism of capsid disassembly in hepatitis B virus

2021 ◽  
Vol 118 (36) ◽  
pp. e2102530118
Author(s):  
Zhaleh Ghaemi ◽  
Martin Gruebele ◽  
Emad Tajkhorshid
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hot Spots ◽  
Hot Spot ◽  
Genetic Material ◽  
Dynamics Simulation ◽  
Small Subset ◽  
B Virus ◽  
Structural Fluctuations ◽  
Capsid Disassembly

The disassembly of a viral capsid leading to the release of its genetic material into the host cell is a fundamental step in viral infection. In hepatitis B virus (HBV), the capsid consists of identical protein monomers that dimerize and then arrange themselves into pentamers or hexamers on the capsid surface. By applying atomistic molecular dynamics simulation to an entire solvated HBV capsid subjected to a uniform mechanical stress protocol, we monitor the capsid-disassembly process and analyze the process down to the level of individual amino acids in 20 independent simulation replicas. The strain of an isotropic external force, combined with structural fluctuations, causes structurally heterogeneous cracks to appear in the HBV capsid. Analysis of the monomer–monomer interfaces reveals that, in contrast to the expectation from purely mechanical considerations, the cracks mainly occur within hexameric sites, whereas pentameric sites remain largely intact. Only a small subset of the capsid protein monomers, different in each simulation, are engaged in each instance of disassembly. We identify specific residues whose interactions are most readily lost during disassembly; R127, I139, Y132, N136, A137, and V149 are among the hot spots at the interfaces between dimers that lie within hexamers, leading to disassembly. The majority of these hot-spot residues are conserved by evolution, hinting to their importance for disassembly by avoiding overstabilization of capsids.

scholarly journals Molecular Mechanism of Capsid Disassembly in Hepatitis B Virus

2021 ◽  
Author(s):  
Zhaleh Ghaemi ◽  
Martin Gruebele ◽  
Emad Tajkhorshid
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Capsid Protein ◽  
Chronic Infection ◽  
Genetic Material ◽  
Thermal Fluctuations ◽  
Dynamics Simulation ◽  
Viral Capsid ◽  
B Virus ◽  
Capsid Disassembly

AbstractThe disassembly of a viral capsid leading to the release of its genetic material into the host cell is a fundamental step in viral infection. Hepatitis B virus (HBV) in particular consists of identical capsid protein monomers that dimerize and also arrange themselves into pentamers or hexamers on the capsid surface. By applying atomistic molecular dynamics simulation to an entire solvated HBV capsid subject to a uniform mechanical stress protocol, we monitor the disassembly process down to the level of individual amino acids. The strain of an external force combined with thermal fluctuations causes structurally heterogeneous cracks to appear in the HBV capsid. Unlike the expectation from purely mechanical considerations, the cracks mainly occur within and between hexameric sites, whereas pentameric sites remain largely intact. Only a small subset of the capsid protein monomers governs disassembly. These monomers are distributed across the whole capsid, but belong to regions with a high degree of collective motion that we label ‘communities’. Cross-talk within these communities is a mechanism of crack propagation leading to destabilization of the entire capsid, and eventually its disassembly. We identify specific residues whose interactions are most readily lost during disassembly: R127, I139, Y132, N136, A137, and V149 are among the hotspots at the interfaces between dimers that lie within or span hexamers, leading to dissociation. The majority of these hotspots are evolutionary conserved, indicating that they are important for disassembly by avoiding over-stabilization of capsids.SignificanceHepatitis B virus (HBV) is a DNA virus that is 100 times more infectious than HIV. Despite the availability of a vaccine, the chronic infection rate of this virus is still about 300 million people globally. HBV chronic infection, for which no cure is currently available, can lead to liver cancer. Therefore, there is an unmet need to investigate the infection cycle of the virus. One of the most crucial steps in virus replication cycle is the release of its genetic material to the nucleus. During this step, the viral capsid enclosing the genetic material disassembles. However, its mechanism is unknown. Here, we utilize molecular simulations to shed light on the events leading to the capsid disassembly with atomistic detail.

scholarly journals A pocket-factor–triggered conformational switch in the hepatitis B virus capsid

2021 ◽  
Vol 118 (17) ◽  
pp. e2022464118
Author(s):  
Lauriane Lecoq ◽  
Shishan Wang ◽  
Marie Dujardin ◽  
Peter Zimmermann ◽  
Leonard Schuster ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Core Protein ◽  
Hot Spot ◽  
Protein A ◽  
Structural Variations ◽  
Interaction Hypothesis ◽  
B Virus ◽  
Alternative Conformation ◽  
Main Culprit

Viral hepatitis is growing into an epidemic illness, and it is urgent to neutralize the main culprit, hepatitis B virus (HBV), a small-enveloped retrotranscribing DNA virus. An intriguing observation in HB virion morphogenesis is that capsids with immature genomes are rarely enveloped and secreted. This prompted, in 1982, the postulate that a regulated conformation switch in the capsid triggers envelopment. Using solid-state NMR, we identified a stable alternative conformation of the capsid. The structural variations focus on the hydrophobic pocket of the core protein, a hot spot in capsid–envelope interactions. This structural switch is triggered by specific, high-affinity binding of a pocket factor. The conformational change induced by the binding is reminiscent of a maturation signal. This leads us to formulate the “synergistic double interaction” hypothesis, which explains the regulation of capsid envelopment and indicates a concept for therapeutic interference with HBV envelopment.

scholarly journals Identification of Hepatitis B virus putative intergenotype recombinants by using fragment typing

2006 ◽  
Vol 87 (8) ◽  
pp. 2203-2215 ◽  
Author(s):  
Jie Yang ◽  
Ke Xing ◽  
Riqiang Deng ◽  
Jinwen Wang ◽  
Xunzhang Wang
Keyword(s):  
Phylogenetic Analysis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hot Spots ◽  
Phylogenetic Analyses ◽  
The Other ◽  
Consensus Sequences ◽  
B Virus ◽  
First Time ◽  
Recombination Breakpoints

Eight hundred and thirty-seven human Hepatitis B virus (HBV) genomes were categorized into pure genotypes and potential intergenotypes, according to their fragment types which were determined based on similarity and phylogenetic analyses of 13 contrived fragments of 250 bp against the corresponding fragments of the consensus sequences of genotypes A–H. Twenty-five intergenotypes, including 171 genomes, were revealed from the potential intergenotype recombinants by phylogenetic analysis of the precisely derived mosaic fragments. Among these, four new intergenotypes were discovered. Many genomes were revealed as putative intergenotype recombinants for the first time. About 87 % of the putative recombinants were B/C (120) and A/D (29) hybrids. The other recombinants comprised A/B/C, A/C, A/E, A/G, C/D, C/F, C/G, C/U (U for unknown genotype) and B/C/U hybrids. Genotypes A and C showed a higher recombination tendency than did other genotypes. The results also demonstrated region priority and breakpoint hot spots in the intergenotype recombination. Recombination breakpoints were found to be concentrated mainly in the vicinity of the DR1 region (nt 1640–1900), the pre S1/S2 region (nt 3150–100), the 3′-end of the C gene (nt 2330–2450) and the 3′-end of the S gene (nt 650–830). These results support the suggestion that intergenotype recombinants may result from co-infection with different genotypes.

scholarly journals ATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure Regimens

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Katherine E. Squires ◽  
Douglas L. Mayers ◽  
Gregory R. Bluemling ◽  
Alexander A. Kolykhalov ◽  
David B. Guthrie ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Small Subset ◽  
Resistance Mutations ◽  
Skeletal Myopathy ◽  
B Virus ◽  
Inhibitor Resistance ◽  
Hbv Model

ABSTRACT ATI-2173 is a novel liver-targeted molecule designed to deliver the 5′-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5′-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development. ATI-2173 was designed by modifying clevudine with a 5′-phosphoramidate to deliver the 5′-monophosphate to the liver. Bypassing the first phosphorylation step of clevudine, the 5′-monophosphate is converted to the active 5′-triphosphate in the liver. ATI-2173 is a selective inhibitor of HBV with an anti-HBV 50% effective concentration (EC50) of 1.31 nM in primary human hepatocytes, with minimal to no toxicity in hepatocytes, skeletal muscle, liver, kidney, bone marrow, and cardiomyocytes. ATI-2173 activity was decreased by viral polymerase mutations associated with entecavir, lamivudine, and adefovir resistance, but not capsid inhibitor resistance mutations. A single oral dose of ATI-2173 demonstrated 82% hepatic extraction, no food effect, and greatly reduced peripheral exposure of clevudine compared with equimolar oral dosing of clevudine. Despite reduced plasma clevudine exposure, liver concentrations of the 5′-triphosphate were equivalent following ATI-2173 versus clevudine administration. By selectively delivering the 5′-monophosphate to the liver, while retaining the unique anti-HBV activity of the 5′-triphosphate, ATI-2173 may provide an improved pharmacokinetic profile for clinical use, reducing systemic exposure of clevudine and potentially eliminating skeletal myopathy.

scholarly journals Genotypes and Hot Spot Mutations of Hepatitis B Virus in Northwest Chinese Population and Its Correlation with Diseases Progression

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Wei Wang ◽  
Yi Shu ◽  
Han Bao ◽  
Wenliang Zhao ◽  
Weihua Wang ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Chinese Population ◽  
Hot Spot ◽  
Chinese Patients ◽  
Basal Core Promoter ◽  
Hbv Genotypes ◽  
Increased Risk ◽  
B Virus ◽  
Genetic Features

Hepatitis B virus (HBV) infection is a critical incentive for chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Different genotypes and genome mutations of HBV have been found to be related to the progression of these liver diseases. However, their clinical significance is still under debate. The objective of this study was to determine the association of HBV genotypes and hot spot mutations in the reverse transcriptase (RT) and basal core promoter-precore (BCP-PreC) region with HBV-infected diseases in a northwest Chinese population. HBV genotyping and DNA sequencing were performed in samples of 980 patients. Appropriate statistical methods were adopted to assess HBV genetic features and its clinical association. It was found that the prevalent HBV genotype in northwestern Chinese patients was HBV/C (61.33%), followed by HBV/B (36.63%). In RT region, in addition to the reported nucleoside analogue- (NA-) resistance missense mutations, new silent mutations at rt169 and rt180 were found to raise the risk of HCC in patients with HBV/C. And the heterozygous mutation status of rt169/rt180 was associated with the increased risk of both HCC and NA resistance (OR > 1, P<0.01) regardless of HBV genotypes. In BCP-PreC region, multiple mutations and combinations, especially at nt 1762/1764 and nt 1896/1899, were characterized to be the causes of spurious HBeAg negativity and liver function injury, as well as the risk factors for HCC progression (P<0.01). Additionally, a novel mutation at nt1799G>C was likely found to increase the risk of HCC in patients with HBV/B. These findings revealed an association between HBV genotypes and HBV genetic mutations in RT and BCP-PreC region and progression of hepatitis B. It would be helpful for risk evaluation and diagnostic improvement based on these genetic features.

scholarly journals Microscopic Characterization of Hepatitis B Virus Capsid Disassembly

2020 ◽  
Vol 118 (3) ◽  
pp. 518a
Author(s):  
Zhaleh Ghaemi ◽  
Martin Gruebele ◽  
Emad Tajkhorshid
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Virus Capsid ◽  
B Virus ◽  
Capsid Disassembly
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