Inhibition of Hepatitis B Virus Replication by Drug-Induced Depletion of Nucleocapsids

Deres, Karl; Schröder, Claus H.; Paessens, Arnold; Goldmann, Siegfried; Hacker, Hans Jörg; Weber, Olaf; Krämer, Thomas; Niewöhner, Ulrich; Pleiß, U.; Stoltefuß, J.; Graef, Erwin; Koletzki, Diana; Masantschek, Ralf N. A.; Reimann, Anja; Jaeger, Rainer; Gross, R. S.; Beckermann, Bernhard; Schlemmer, Karl‐Heinz; Haebich, Dieter; Rübsamen‐Waigmann, Helga

doi:10.1126/science.1077215

Cited by 472 publications

(398 citation statements)

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“…Thus assuming that misfolded proteins are not all destroyed and consequently that some are used by the virus, misfolding can lead to increases in c and reductions in k. If a virus has adapted to reduce the antigenicity of its envelope proteins, misfolded proteins could lead to greater antibody binding to free virus, which would in turn lead to an increase in the virion's average clearance rate c. Similarly, misfolded envelope proteins would be expected to have a lower target cell binding rate, thus directly decreasing k. Finally, misfolded viral proteins involved in post cell-invasion processes, such as reverse transcription, should have lower enzymatic activities and shorter intracellular half-lives (and hence concentrations). Thus, misfolded proteins could also indirectly reduce the average rate of successful infection, k. The effect of reducing the intracellular half-life of hepatitis B virus core protein has recently been reported to have a substantial antiviral effect (Deres et al, 2003).…”

Section: Linking Production To Other Termsmentioning

confidence: 99%

Optimizing within-host viral fitness: infected cell lifespan and virion production rate

Gilchrist

Coombs

Perelson

2004

Journal of Theoretical Biology

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We explore how an infected cell's virion production rate can affect the relative fitness of a virus within a host. We perform an invasion analysis, based on an age-structured model of viral dynamics, to derive the within-host relative viral fitness. We find that for chronic infections, in the absence of trade-offs between viral life history stages, natural selection favors viral strains whose virion production rate maximizes viral burst size. We then show how various life history trade-offs such as that between virion production and immune system recognition and clearance of virally infected cells can lead to natural selection favoring production rates lower than the one that maximizes burst size. Our findings suggest that HIV replication rates should vary between cells with different life spans, as has been suggested by recent observation. Published by Elsevier Ltd.

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Section: Linking Production To Other Termsmentioning

confidence: 99%

Optimizing within-host viral fitness: infected cell lifespan and virion production rate

Gilchrist

Coombs

Perelson

2004

Journal of Theoretical Biology

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“…HBV transgenic animals (kindly provided by H Schaller, Heidelberg, Germany) replicate HBV in hepatocytes from an integrated 1.3 over-length genome carrying a frameshift mutation in the 3 0 and 5 0 copy of the HBV X gene resulting in a premature stop codon. 52 To generate double transgenic mice, rTA LAP -1 mice and HBV1.3xfs mice were bred homozygously and crossed with each other. Offspring that were heterozygous for both transgenes were used for the experiments.…”

Section: Mouse Linesmentioning

confidence: 99%

Liver-specific expression of interferon γ following adenoviral gene transfer controls hepatitis B virus replication in mice

et al. 2005

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Interferons control viral replication and the growth of some malignant tumors. Since systemic application may cause severe adverse effects, tissue-specific expression is an attractive alternative. Liver-directed interferon gene therapy offers promising applications such as chronic viral hepatitis B or C or hepatocellular carcinoma and thus needs testing in vivo in suitable animal models. We therefore used the Tet-On system to regulate gene expression in adenoviral vectors, and studied the effect of liver-specific and regulated interferon g expression in a mouse model of chronic hepatitis B virus (HBV) infection. In a first generation adenoviral vector, genes encoding for firefly luciferase and interferons a, b or g, respectively, were coexpressed under control of the bidirectional tetracycline-regulated promoter P tet bi. Liverspecific promoters driving expression of the reverse tetracycline controlled transactivator ensured local expression in the livers of HBV transgenic mice. Following gene transfer, we demonstrated low background, tight regulation and a 1000-fold induction of gene expression by doxycycline. Both genes within the bidirectional transcription unit were expressed simultaneously, and in a liver-specific fashion in cell culture and in living mice. Doxycycline-dependent interferon g expression effectively controlled HBV replication in mice, but did not eliminate HBV transcripts. This system will help to study the effects of local cytokine expression in mouse disease models in detail. Gene Therapy (2005) 12, 668-677.

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“…Disruption of capsid reorganization can be an effective approach to viral inhibition, with examples including targeting of capsid assembly in Hepatitis B Virus (HBV) 25 and blocking of capsid disassembly in picorona viruses 26 . Support for this approach for HIV-1 was provided by CAI, a peptide inhibitor of CA C -CA C interactions that inhibits immature and mature particle formation in vitro 27; 28 , although CAI was unable to inhibit the release of HIV-1 particles when added to virus producing cells in cell culture or by peptide transfection.…”

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confidence: 99%

Structure of the Antiviral Assembly Inhibitor CAP-1 Complex with the HIV-1 CA Protein

Kelly

Kyere

Kinde

et al. 2007

Journal of Molecular Biology

140

161

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The CA domain of the HIV-1 Gag polyprotein plays critical roles in both the early and late phases of viral replication and is therefore an attractive antiviral target. Compounds with antiviral activity were recently identified that bind to the N-terminal domain of CA (CA N ) and inhibit core assembly during viral maturation. We have determined the structure of the complex between CA N and the antiviral assembly inhibitor N-(3-chloro-4-methylphenyl)-N'-{2-[({5-[(dimethylamino)-methyl]-2-furyl}-methyl)-sulfanyl]ethyl}-urea) (CAP-1) using a combination of NMR spectroscopy and X-ray crystallography. The protein undergoes a remarkable conformational change upon CAP-1 binding, in which Phe32 is displaced from its buried position in the protein core to open a deep hydrophobic cavity that serves as the ligand binding site. The aromatic ring of CAP-1 inserts into the cavity, with the urea NH groups forming hydrogen bonds with the backbone oxygen of Val59 and the dimethylamino group interacting with the side chains of Glu28 and Glu29. Elements that could be exploited to improve binding affinity are apparent in the structure. The displacement of Phe32 by CAP-1 appears to be facilitated by a strained main chain conformation, which suggests a potential role for a Phe32 conformational switch during normal capsid assembly.The AIDS epidemic continues to be a significant international health problem, with approximately 40 million people living with HIV infection world-wide 1 . In 2006 alone, 4.3 million individuals became infected with HIV, and approximately 3 million deaths were attributed to AIDS. Therapeutic agents currently used to treat HIV infection target the viral reverse transcriptase, protease, and fusion proteins, and drugs that target the integrase enzyme are undergoing clinical trials (www.aidsinfo.nih.gov). Although sustained reductions in viral load can be achieved for many years with combination drug therapies 2; 3; 4 , inadequate suppression due to poor compliance, resistance, and interactions with other drugs or diet can be a significant problem for some patients and can lead to the spread of drug-resistant strains = These authors contributed equally to this work. * To whom correspondence should be addressed: W.I.S.: tel, 801-585-5402; e-mail, wes@biochem.utah.edu. M.F.S: tel 410-455-2880; e-mail summers@hhmi.umbc.edu. C.P.H: tel, 801-585-5536; e-mail, chris@biochem.utah.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The CA protein plays critical roles in the early and late phases of replication and has long been considered an attractive potential therapeuti...

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Inhibition of Hepatitis B Virus Replication by Drug-Induced Depletion of Nucleocapsids

Cited by 472 publications

References 10 publications

Optimizing within-host viral fitness: infected cell lifespan and virion production rate

Optimizing within-host viral fitness: infected cell lifespan and virion production rate

Liver-specific expression of interferon γ following adenoviral gene transfer controls hepatitis B virus replication in mice

Structure of the Antiviral Assembly Inhibitor CAP-1 Complex with the HIV-1 CA Protein

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