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  1. Article ; Online: Taking cues from convalescence to improve vaccines against hepatitis C virus.

    Sreekumar, Bharath K / Taha, Taha Y / Ott, Melanie

    The Journal of clinical investigation

    2022  Volume 132, Issue 15

    Abstract: Hepatitis C virus (HCV) infection remains a worldwide public health issue despite direct-acting antivirals. A substantial proportion of infected individuals (15%-45%) spontaneously clear repeated HCV infections with genetically different viruses by ... ...

    Abstract Hepatitis C virus (HCV) infection remains a worldwide public health issue despite direct-acting antivirals. A substantial proportion of infected individuals (15%-45%) spontaneously clear repeated HCV infections with genetically different viruses by generating broadly neutralizing antibodies (bNAbs). However, translating this response into an effective vaccine strategy has been unsuccessful. In this issue of the JCI, Frumento and colleagues report on their study of bNAb evolution longitudinally in convalescent individuals with repeated infections. Using pseudotyped viruses, well-characterized monoclonal antibodies, and complex modeling, the authors show that multiple exposures to antigenically related, antibody-sensitive viral envelope proteins induced potent bNAbs. This work provides valuable insight into the best strategies for developing HCV vaccines in the future that may successfully reproduce the immunity induced during natural exposures.
    MeSH term(s) Antibodies, Neutralizing ; Antiviral Agents ; Broadly Neutralizing Antibodies ; Convalescence ; Cues ; Hepacivirus ; Hepatitis C ; Hepatitis C Antibodies ; Hepatitis C, Chronic ; Humans ; Vaccines/metabolism ; Viral Envelope Proteins ; Viral Hepatitis Vaccines
    Chemical Substances Antibodies, Neutralizing ; Antiviral Agents ; Broadly Neutralizing Antibodies ; Hepatitis C Antibodies ; Vaccines ; Viral Envelope Proteins ; Viral Hepatitis Vaccines
    Language English
    Publishing date 2022-08-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI161819
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Design and Optimization of a

    Taha, Taha Y / Townsend, Michael B / Pohl, Jan / Karem, Kevin L / Damon, Inger K / Mbala Kingebeni, Placide / Muyembe Tamfum, Jean-Jacques / Martin, James W / Pittman, Phillip R / Huggins, John W / Satheshkumar, Panayampalli S / Bagarozzi, Dennis A / Reynolds, Mary G / Hughes, Laura J

    Pathogens (Basel, Switzerland)

    2023  Volume 12, Issue 3

    Abstract: Monkeypox virus (MPXV), a member of ... ...

    Abstract Monkeypox virus (MPXV), a member of the
    Language English
    Publishing date 2023-03-01
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2695572-6
    ISSN 2076-0817
    ISSN 2076-0817
    DOI 10.3390/pathogens12030396
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: A single inactivating amino acid change in the SARS-CoV-2 NSP3 Mac1 domain attenuates viral replication and pathogenesis

    Taha, Taha Y / Suryawanshi, Rahul K / Chen, Irene P / Correy, Galen J / O'Leary, Patrick C / Jogalekar, Manasi P / McCavitt-Malvido, Maria / Diolaiti, Morgan E / Kimmerly, Gabriella R / Tsou, Chia-Lin / Martinez-Sobrido, Luis / Krogan, Nevan J / Ashworth, Alan / Fraser, James S / Ott, Melanie

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Despite unprecedented efforts, our therapeutic arsenal against SARS-CoV-2 remains limited. The conserved macrodomain 1 (Mac1) in NSP3 is an enzyme exhibiting ADP-ribosylhydrolase activity and a possible drug target. To determine the therapeutic potential ...

    Abstract Despite unprecedented efforts, our therapeutic arsenal against SARS-CoV-2 remains limited. The conserved macrodomain 1 (Mac1) in NSP3 is an enzyme exhibiting ADP-ribosylhydrolase activity and a possible drug target. To determine the therapeutic potential of Mac1 inhibition, we generated recombinant viruses and replicons encoding a catalytically inactive NSP3 Mac1 domain by mutating a critical asparagine in the active site. While substitution to alanine (N40A) reduced catalytic activity by ~10-fold, mutations to aspartic acid (N40D) reduced activity by ~100-fold relative to wildtype. Importantly, the N40A mutation rendered Mac1 unstable
    Language English
    Publishing date 2023-05-10
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.04.18.537104
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Modulation of hepatitis B virus pregenomic RNA stability and splicing by histone deacetylase 5 enhances viral biosynthesis.

    Taha, Taha Y / Anirudhan, Varada / Limothai, Umaporn / Loeb, Daniel D / Petukhov, Pavel A / McLachlan, Alan

    PLoS pathogens

    2020  Volume 16, Issue 8, Page(s) e1008802

    Abstract: Hepatitis B virus (HBV) is a worldwide health problem without curative treatments. Investigation of the regulation of HBV biosynthesis by class I and II histone deacetylases (HDACs) demonstrated that catalytically active HDAC5 upregulates HBV ... ...

    Abstract Hepatitis B virus (HBV) is a worldwide health problem without curative treatments. Investigation of the regulation of HBV biosynthesis by class I and II histone deacetylases (HDACs) demonstrated that catalytically active HDAC5 upregulates HBV biosynthesis. HDAC5 expression increased both the stability and splicing of the HBV 3.5 kb RNA without altering the translational efficiency of the viral pregenomic or spliced 2.2 kb RNAs. Together, these observations point to a broader role of HDAC5 in regulating RNA splicing and transcript stability while specifically identifying a potentially novel approach toward antiviral HBV therapeutic development.
    MeSH term(s) Gene Expression Regulation, Viral ; Genome, Viral ; Hep G2 Cells ; Hepatitis B/virology ; Hepatitis B virus/genetics ; Hepatitis B virus/metabolism ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Humans ; RNA Stability ; RNA, Viral/biosynthesis ; RNA, Viral/chemistry ; Transcription, Genetic ; Virus Replication
    Chemical Substances RNA, Viral ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2020-08-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7366
    ISSN (online) 1553-7374
    ISSN 1553-7366
    DOI 10.1371/journal.ppat.1008802
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Histone deacetylase inhibitor-based chromatin precipitation for identification of targeted genomic loci.

    Hanigan, Thomas W / Danes, Jeanne M / Taha, Taha Y / Frasor, Jonna / Petukhov, Pavel A

    Journal of biological methods

    2017  Volume 5, Issue 1

    Abstract: Histone deacetylase (HDAC) catalyzes the removal of acetyl marks from histones, effectively regulating gene expression. Genome wide chromatin immunoprecipitation (ChIP) studies have shown HDACs are present on numerous active and repressed genes. However, ...

    Abstract Histone deacetylase (HDAC) catalyzes the removal of acetyl marks from histones, effectively regulating gene expression. Genome wide chromatin immunoprecipitation (ChIP) studies have shown HDACs are present on numerous active and repressed genes. However, HDAC inhibitors (HDACi) only regulate a small subset of this population in a cell type dependent fashion. To determine genomic locations directly targeted by HDACi, we developed a chromatin precipitation method using a photoreactive HDAC inhibitor probe (photomate). We validate this method by analyzing several canonical HDACi regulated genes, CDKN1A and FOSL1, and compare it to traditional ChIP using HDAC1 antibodies. We show that HDACi target HDACs bound at the promoter regions but not gene bodies, differing from HDAC1 antibody-based ChIP in the case of CDKN1A. This approach is anticipated to be useful for genome wide studies to identify the subset of genes directly regulated by an HDACi in a given cell type.
    Language English
    Publishing date 2017-02-09
    Publishing country United States
    Document type Journal Article
    ISSN 2326-9901
    ISSN 2326-9901
    DOI 10.14440/jbm.2018.216
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Rapid assembly of SARS-CoV-2 genomes reveals attenuation of the Omicron BA.1 variant through NSP6.

    Taha, Taha Y / Chen, Irene P / Hayashi, Jennifer M / Tabata, Takako / Walcott, Keith / Kimmerly, Gabriella R / Syed, Abdullah M / Ciling, Alison / Suryawanshi, Rahul K / Martin, Hannah S / Bach, Bryan H / Tsou, Chia-Lin / Montano, Mauricio / Khalid, Mir M / Sreekumar, Bharath K / Renuka Kumar, G / Wyman, Stacia / Doudna, Jennifer A / Ott, Melanie

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 2308

    Abstract: Although the SARS-CoV-2 Omicron variant (BA.1) spread rapidly across the world and effectively evaded immune responses, its viral fitness in cell and animal models was reduced. The precise nature of this attenuation remains unknown as generating ... ...

    Abstract Although the SARS-CoV-2 Omicron variant (BA.1) spread rapidly across the world and effectively evaded immune responses, its viral fitness in cell and animal models was reduced. The precise nature of this attenuation remains unknown as generating replication-competent viral genomes is challenging because of the length of the viral genome (~30 kb). Here, we present a plasmid-based viral genome assembly and rescue strategy (pGLUE) that constructs complete infectious viruses or noninfectious subgenomic replicons in a single ligation reaction with >80% efficiency. Fully sequenced replicons and infectious viral stocks can be generated in 1 and 3 weeks, respectively. By testing a series of naturally occurring viruses as well as Delta-Omicron chimeric replicons, we show that Omicron nonstructural protein 6 harbors critical attenuating mutations, which dampen viral RNA replication and reduce lipid droplet consumption. Thus, pGLUE overcomes remaining barriers to broadly study SARS-CoV-2 replication and reveals deficits in nonstructural protein function underlying Omicron attenuation.
    MeSH term(s) Animals ; Coronavirus Nucleocapsid Proteins/genetics ; COVID-19 ; Genome, Viral/genetics ; RNA, Viral/genetics ; SARS-CoV-2/genetics ; Subgenomic RNA/genetics
    Chemical Substances Coronavirus Nucleocapsid Proteins ; NSP6 protein, SARS-CoV-2 ; RNA, Viral ; Subgenomic RNA
    Language English
    Publishing date 2023-04-21
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-37787-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Rapid assembly of SARS-CoV-2 genomes reveals attenuation of the Omicron BA.1 variant through NSP6.

    Taha, Taha Y / Chen, Irene P / Hayashi, Jennifer M / Tabata, Takako / Walcott, Keith / Kimmerly, Gabriella R / Syed, Abdullah M / Ciling, Alison / Suryawanshi, Rahul K / Martin, Hannah S / Bach, Bryan H / Tsou, Chia-Lin / Montano, Mauricio / Khalid, Mir M / Sreekumar, Bharath K / Kumar, G Renuka / Wyman, Stacia / Doudna, Jennifer A / Ott, Melanie

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Although the SARS-CoV-2 Omicron variant (BA.1) spread rapidly across the world and effectively evaded immune responses, its viral fitness in cell and animal models was reduced. The precise nature of this attenuation remains unknown as generating ... ...

    Abstract Although the SARS-CoV-2 Omicron variant (BA.1) spread rapidly across the world and effectively evaded immune responses, its viral fitness in cell and animal models was reduced. The precise nature of this attenuation remains unknown as generating replication-competent viral genomes is challenging because of the length of the viral genome (30kb). Here, we designed a plasmid-based viral genome assembly and resc ue strategy (pGLUE) that constructs complete infectious viruses or noninfectious subgenomic replicons in a single ligation reaction with >80% efficiency. Fully sequenced replicons and infectious viral stocks can be generated in 1 and 3 weeks, respectively. By testing a series of naturally occurring viruses as well as Delta-Omicron chimeric replicons, we show that Omicron nonstructural protein 6 harbors critical attenuating mutations, which dampen viral RNA replication and reduce lipid droplet consumption. Thus, pGLUE overcomes remaining barriers to broadly study SARS-CoV-2 replication and reveals deficits in nonstructural protein function underlying Omicron attenuation.
    Language English
    Publishing date 2023-02-09
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.01.31.525914
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: The Regulation of HBV Transcription and Replication.

    Oropeza, Claudia E / Tarnow, Grant / Sridhar, Abhayavarshini / Taha, Taha Y / Shalaby, Rasha E / McLachlan, Alan

    Advances in experimental medicine and biology

    2019  Volume 1179, Page(s) 39–69

    Abstract: Hepatitis B virus (HBV) is a major human pathogen lacking a reliable curative therapy. Current therapeutics target the viral reverse transcriptase/DNA polymerase to inhibit viral replication but generally fail to resolve chronic HBV infections. Due to ... ...

    Abstract Hepatitis B virus (HBV) is a major human pathogen lacking a reliable curative therapy. Current therapeutics target the viral reverse transcriptase/DNA polymerase to inhibit viral replication but generally fail to resolve chronic HBV infections. Due to the limited coding potential of the HBV genome, alternative approaches for the treatment of chronic infections are desperately needed. An alternative approach to the development of antiviral therapeutics is to target cellular gene products that are critical to the viral life cycle. As transcription of the viral genome is an essential step in the viral life cycle, the selective inhibition of viral RNA synthesis is a possible approach for the development of additional therapeutic modalities that might be used in combination with currently available therapies. To address this possibility, a molecular understanding of the relationship between viral transcription and replication is required. The first step is to identify the transcription factors that are the most critical in controlling the levels of HBV RNA synthesis and to determine their in vivo role in viral biosynthesis. Mapping studies in cell culture utilizing reporter gene constructs permitted the identification of both ubiquitous and liver-enriched transcription factors capable of modulating transcription from the four HBV promoters. However, it was challenging to determine their relative importance for viral biosynthesis in the available human hepatoma replication systems. This technical limitation was addressed, in part, by the development of non-hepatoma HBV replication systems where viral biosynthesis was dependent on complementation with exogenously expressed transcription factors. These systems revealed the importance of specific nuclear receptors and hepatocyte nuclear factor 3 (HNF3)/forkhead box A (FoxA) transcription factors for HBV biosynthesis. Furthermore, using the HBV transgenic mouse model of chronic viral infection, the importance of various nuclear receptors and FoxA isoforms could be established in vivo. The availability of this combination of systems now permits a rational approach toward the development of selective host transcription factor inhibitors. This might permit the development of a new class of therapeutics to aid in the treatment and resolution of chronic HBV infections, which currently affects approximately 1 in 30 individuals worldwide and kills up to a million people annually.
    MeSH term(s) Animals ; DNA, Viral/chemistry ; Hepatitis B virus/genetics ; Hepatitis B virus/physiology ; Humans ; Mice ; Transcription, Genetic/genetics ; Virus Replication/genetics
    Chemical Substances DNA, Viral
    Language English
    Publishing date 2019-11-18
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2214-8019 ; 0065-2598
    ISSN (online) 2214-8019
    ISSN 0065-2598
    DOI 10.1007/978-981-13-9151-4_3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Relative DNA Methylation and Demethylation Efficiencies during Postnatal Liver Development Regulate Hepatitis B Virus Biosynthesis.

    Oropeza, Claudia E / Tarnow, Grant / Taha, Taha Y / Shalaby, Rasha E / Hyde, Marieta V / Maienschein-Cline, Mark / Green, Stefan J / McLachlan, Alan

    Journal of virology

    2021  Volume 95, Issue 6

    Abstract: Hepatitis B virus (HBV) transcription and replication increase progressively throughout postnatal liver development with maximal viral biosynthesis occurring at around 4 weeks of age in the HBV transgenic mouse model of chronic infection. Increasing ... ...

    Abstract Hepatitis B virus (HBV) transcription and replication increase progressively throughout postnatal liver development with maximal viral biosynthesis occurring at around 4 weeks of age in the HBV transgenic mouse model of chronic infection. Increasing viral biosynthesis is associated with a corresponding progressive loss of DNA methylation. The loss of DNA methylation is associated with increasing levels of 5-hydroxymethylcytosine (5hmC) residues which correlate with increased liver-enriched pioneer transcription factor Forkhead box protein A (FoxA) RNA levels, a rapid decline in postnatal liver DNA methyltransferase (Dnmt) transcripts, and a very modest reduction in ten-eleven translocation (Tet) methylcytosine dioxygenase expression. These observations are consistent with the suggestion that the balance between active HBV DNA methylation and demethylation is regulated by FoxA recruitment of Tet in the presence of declining Dnmt activity. These changes lead to demethylation of the viral genome during hepatocyte maturation with associated increases in viral biosynthesis. Consequently, manipulation of the relative activities of these two counterbalancing processes might permit the specific silencing of HBV gene expression with the loss of viral biosynthesis and the resolution of chronic HBV infections.
    MeSH term(s) 5-Methylcytosine/analogs & derivatives ; 5-Methylcytosine/metabolism ; Animals ; Animals, Newborn ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; DNA Methylation ; DNA Replication ; DNA, Viral/biosynthesis ; DNA, Viral/metabolism ; Demethylation ; Dioxygenases/genetics ; Dioxygenases/metabolism ; Disease Models, Animal ; Gene Expression Regulation, Developmental ; Gene Expression Regulation, Viral ; Hepatitis B virus/physiology ; Hepatitis B, Chronic/metabolism ; Hepatitis B, Chronic/pathology ; Hepatitis B, Chronic/virology ; Hepatocyte Nuclear Factors/genetics ; Hepatocyte Nuclear Factors/metabolism ; Liver/growth & development ; Liver/metabolism ; Liver/virology ; Mice ; Mice, Transgenic ; RNA, Viral/biosynthesis ; Virus Replication
    Chemical Substances DNA, Viral ; Hepatocyte Nuclear Factors ; RNA, Viral ; 5-hydroxymethylcytosine (1123-95-1) ; 5-Methylcytosine (6R795CQT4H) ; Dioxygenases (EC 1.13.11.-) ; Tet3 protein, mouse (EC 1.13.11.-) ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37)
    Language English
    Publishing date 2021-02-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.02148-20
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Scaffold dependent histone deacetylase (HDAC) inhibitor induced re-equilibration of the subcellular localization and post-translational modification state of class I HDACs.

    Hanigan, Thomas W / Taha, Taha Y / Aboukhatwa, Shaimaa M / Frasor, Jonna / Petukhov, Pavel A

    PloS one

    2017  Volume 12, Issue 10, Page(s) e0186620

    Abstract: The mechanism of action of histone deacetylase inhibitors (HDACi) is mainly attributed to the inhibition of the deacetylase catalytic activity for their histone substrates. In this study, we analyzed the abundance of class I HDACs in the cytosolic, ... ...

    Abstract The mechanism of action of histone deacetylase inhibitors (HDACi) is mainly attributed to the inhibition of the deacetylase catalytic activity for their histone substrates. In this study, we analyzed the abundance of class I HDACs in the cytosolic, nuclear soluble and chromatin bound cellular fractions in breast cancer cells after HDACi treatment. We found that potent N-hydroxy propenamide-based HDACi induced a concentration dependent decrease in the HDAC1 associated with chromatin and a lasting concomitant increase in cytoplasmic HDAC1 while maintaining total protein expression. No such change occurred with HDAC2 or 8, however, an increase in cytoplasmic non-phosphorylated HDAC3 was also observed. The subcellular re-equilibration of HDAC1 was subsequent to the accumulation of acetylated histones and might be cell cycle dependent. This study suggests that the biological activity of a subset of N-hydroxy propenamide-based HDACi may stem from direct competition with histone substrates of HDACs as well as from spatial separation from their substrates in the nucleus and/or change in post-translational modification status of HDACs.
    MeSH term(s) Acetylation/drug effects ; Cytosol/drug effects ; Cytosol/enzymology ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/metabolism ; Histones/metabolism ; Humans ; MCF-7 Cells ; Microscopy, Confocal ; Mitogens/pharmacology ; Models, Biological ; Phosphorylation/drug effects ; Protein Processing, Post-Translational/drug effects ; Protein Transport/drug effects ; Subcellular Fractions/drug effects ; Subcellular Fractions/enzymology
    Chemical Substances Histone Deacetylase Inhibitors ; Histones ; Mitogens ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2017-10-18
    Publishing country United States
    Document type Journal Article
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0186620
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