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HIV RNA splicing

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https://www.readbyqxmd.com/read/28250115/viral-epitranscriptomics
#1
Edward M Kennedy, David G Courtney, Kevin Tsai, Bryan R Cullen
Although it has been known for over 40 years that eukaryotic mRNAs bear internal base modifications, it is only in the last five years that the importance of these modifications has begun to come into focus. The most common mRNA modification, the addition of a methyl group to the N(6) position of adenosine (m(6)A), has been shown to affect splicing, translation and stability, and m(6)A is also essential for embryonic development in organisms ranging from plants to mice. While all viral transcripts examined so far have been found to be extensively m(6)A modified, the role, if any, of m(6)A in regulating viral gene expression and replication was previously unknown...
March 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28193894/rules-of-rna-specificity-of-hnrnp-a1-revealed-by-global-and-quantitative-analysis-of-its-affinity-distribution
#2
Niyati Jain, Hsuan-Chun Lin, Christopher E Morgan, Michael E Harris, Blanton S Tolbert
Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a multipurpose RNA-binding protein (RBP) involved in normal and pathological RNA metabolism. Transcriptome-wide mapping and in vitro evolution identify consensus hnRNP A1 binding motifs; however, such data do not reveal how surrounding RNA sequence and structural context modulate affinity. We determined the affinity of hnRNP A1 for all possible sequence variants (n = 16,384) of the HIV exon splicing silencer 3 (ESS3) 7-nt apical loop. Analysis of the affinity distribution identifies the optimal motif 5'-YAG-3' and shows how its copy number, position in the loop, and loop structure modulate affinity...
February 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28153748/a-dead-box-helicase-mediates-an-rna-structural-transition-in-the-hiv-1-rev-response-element
#3
John A Hammond, Rajan Lamichhane, David P Millar, James R Williamson
Nuclear export of partially spliced or unspliced HIV-1 RNA transcripts requires binding of the viral protein regulator of expression of virion (Rev) to the Rev response element (RRE) and subsequent oligomerization in a cooperative manner. Cellular DEAD-box helicase DEAD-box protein 1 (DDX1) plays a role in HIV replication, interacting with and affecting Rev-containing HIV transcripts in vivo, interacting directly with the RRE and Rev in vitro, and promoting Rev oligomerization in vitro. Binding of DDX1 results in enhancement of Rev oligomerization on the RRE that is correlated with an RNA structural change within the RRE that persists even after dissociation of DDX1...
March 10, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28122580/identification-of-small-molecule-modulators-of-hiv-1-tat-and-rev-protein-accumulation
#4
Ahalya Balachandran, Raymond Wong, Peter Stoilov, Sandy Pan, Benjamin Blencowe, Peter Cheung, P Richard Harrigan, Alan Cochrane
BACKGROUND: HIV-1 replication is critically dependent upon controlled processing of its RNA and the activities provided by its encoded regulatory factors Tat and Rev. A screen of small molecule modulators of RNA processing identified several which inhibited virus gene expression, affecting both relative abundance of specific HIV-1 RNAs and the levels of Tat and Rev proteins. RESULTS: The screen for small molecules modulators of HIV-1 gene expression at the post-transcriptional level identified three (a pyrimidin-7-amine, biphenylcarboxamide, and benzohydrazide, designated 791, 833, and 892, respectively) that not only reduce expression of HIV-1 Gag and Env and alter the accumulation of viral RNAs, but also dramatically decrease Tat and Rev levels...
January 26, 2017: Retrovirology
https://www.readbyqxmd.com/read/28077653/characterizing-hiv-1-splicing-by-using-next-generation-sequencing
#5
Ann Emery, Shuntai Zhou, Elizabeth Pollom, Ronald Swanstrom
Full-length human immunodeficiency virus type 1 (HIV-1) RNA serves as the genome or as an mRNA, or this RNA undergoes splicing using four donors and 10 acceptors to create over 50 physiologically relevant transcripts in two size classes (1.8 kb and 4 kb). We developed an assay using Primer ID-tagged deep sequencing to quantify HIV-1 splicing. Using the lab strain NL4-3, we found that A5 (env/nef) is the most commonly used acceptor (about 50%) and A3 (tat) the least used (about 3%). Two small exons are made when a splice to acceptor A1 or A2 is followed by activation of donor D2 or D3, and the high-level use of D2 and D3 dramatically reduces the amount of vif and vpr transcripts...
March 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28003477/argonaute-proteins-regulate-hiv-1-multiply-spliced-rna-and-viral-production-in-a-dicer-independent-manner
#6
Agathe Eckenfelder, Emmanuel Ségéral, Natalia Pinzón, Damien Ulveling, Céline Amadori, Marine Charpentier, Sabine Nidelet, Jean-Paul Concordet, Jean-François Zagury, Jean-Christophe Paillart, Clarisse Berlioz-Torrent, Hervé Seitz, Stéphane Emiliani, Sarah Gallois-Montbrun
Argonaute (Ago) proteins associate with microRNAs (miRNAs) to form the core of the RNA-induced silencing complex (RISC) that mediates post-transcriptional gene silencing of target mRNAs. As key players in anti-viral defense, Ago proteins are thought to have the ability to interact with human immunodeficiency virus type 1 (HIV-1) RNA. However, the role of this interaction in regulating HIV-1 replication has been debated. Here, we used high throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP) to explore the interaction between Ago2 and HIV-1 RNA in infected cells...
December 20, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27940419/novel-clk1-inhibitors-based-on-n-aryloxazol-2-amine-skeleton-a-possible-way-to-dual-vegfr2-tk-clk-ligands
#7
Miroslav Murár, Juraj Dobiaš, Peter Šramel, Gabriela Addová, Gilles Hanquet, Andrej Boháč
BACKGROUND: Inhibitors of CLK protein kinases suppress cell growth and induce apoptosis by modulating pre-mRNA splicing in cancer. CLK family kinases are also involved in alternative splicing and RNA processing in Duchenne muscular dystrophy, Alzheimer's disease, HIV-1, and influenza virus. Small inhibitors are valuable tools for better understanding the molecular mechanisms of splicing and may serve as seeds for a novel class of therapeutics. ACHIEVEMENTS: Here we describe a discovery of four novel CLK1 inhibitors possessing N-aryloxazol-2-amine skeleton...
January 27, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27928057/modulation-of-the-splicing-regulatory-function-of-srsf10-by-a-novel-compound-that-impairs-hiv-1-replication
#8
Lulzim Shkreta, Marco Blanchette, Johanne Toutant, Emmanuelle Wilhelm, Brendan Bell, Benjamin A Story, Ahalya Balachandran, Alan Cochrane, Peter K Cheung, P Richard Harrigan, David S Grierson, Benoit Chabot
We recently identified the 4-pyridinone-benzisothiazole carboxamide compound 1C8 as displaying strong anti-HIV-1 potency against a variety of clinical strains in vitro Here we show that 1C8 decreases the expression of HIV-1 and alters splicing events involved in the production of HIV-1 mRNAs. Although 1C8 was designed to be a structural mimic of the fused tetracyclic indole compound IDC16 that targets SRSF1, it did not affect the splice site shifting activity of SRSF1. Instead, 1C8 altered splicing regulation mediated by SRSF10...
December 7, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27920203/a-highly-active-isoform-of-lentivirus-restriction-factor-samhd1-in-mouse
#9
Nicolin Bloch, Sabine Gläsker, Poojitha Sitaram, Henning Hofmann, Caitlin N Shepard, Megan L Schultz, Baek Kim, Nathaniel R Landau
The triphosphohydrolase SAMHD1 (sterile α motif and histidine-aspartate domain-containing protein 1) restricts HIV-1 replication in nondividing myeloid cells by depleting the dNTP pool, preventing reverse transcription. SAMHD1 is also reported to have ribonuclease activity that degrades the virus genomic RNA. Human SAMHD1 is regulated by phosphorylation of its carboxyl terminus at Thr-592, which abrogates its antiviral function yet has only a small effect on its phosphohydrolase activity. In the mouse, SAMHD1 is expressed as two isoforms (ISF1 and ISF2) that differ at the carboxyl terminus due to alternative splicing of the last coding exon...
January 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27914932/detection-of-human-immunodeficiency-virus-rnas-in-living-cells-using-spinach-rna-aptamers
#10
Brandon D Burch, Carolina Garrido, David M Margolis
Many techniques currently used to measure HIV RNA production in cells suffer from limitations that include high background signal or the potential to destroy cellular context. Fluorophore-binding RNA aptamers offer the potential for visualizing RNAs directly in living cells with minimal cellular perturbation. We inserted a sequence encoding a fluorophore-binding RNA aptamer, known as Spinach, into the HIV genome such that predicted RNA secondary structures in both Spinach and HIV were preserved. Chimeric HIV-Spinach RNAs were functionally validated in vitro by testing their ability to enhance the fluorescence of a conditional fluorophore (DFHBI), which specifically binds Spinach...
January 15, 2017: Virus Research
https://www.readbyqxmd.com/read/27911724/control-of-hiv-1-gene-expression-by-sr-proteins
#11
REVIEW
Charlotte Mahiet, Chad M Swanson
Cellular proteins are required for all steps of human immunodeficiency virus type 1 (HIV-1) gene expression including transcription, splicing, 3'-end formation/polyadenylation, nuclear export and translation. SR proteins are a family of cellular RNA-binding proteins that regulate and functionally integrate multiple steps of gene expression. Specific SR proteins are best characterised for regulating HIV-1 RNA splicing by binding specific locations in the viral RNA, though recently they have also been shown to control transcription, 3'-end formation, and translation...
October 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27721439/hiv-1-vpr-n-terminal-tagging-affects-alternative-splicing-of-the-viral-genome
#12
Ann Baeyens, Evelien Naessens, Anouk Van Nuffel, Karin E Weening, Anne-Marie Reilly, Eva Claeys, Wim Trypsteen, Linos Vandekerckhove, Sven Eyckerman, Kris Gevaert, Bruno Verhasselt
To facilitate studies on Vpr function in replicating HIV-1, we aimed to tag the protein in an infectious virus. First we showed that N-, but not C-terminal HA/FLAG tagging of Vpr protein preserves Vpr cytopathicity. Cloning the tags into proviral DNA however ablated viral production and replication. By construction of additional viral variants we could show this defect was not protein- but RNA-dependent and sequence specific, and characterized by oversplicing of the genomic RNA. Simulation of genomic RNA folding suggested that introduction of the tag sequence induced an alternative folding structure in a region enriched in splice sites and splicing regulatory sequences...
October 10, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27648642/genome-wide-analysis-of-rna-secondary-structure
#13
Philip C Bevilacqua, Laura E Ritchey, Zhao Su, Sarah M Assmann
Single-stranded RNA molecules fold into extraordinarily complicated secondary and tertiary structures as a result of intramolecular base pairing. In vivo, these RNA structures are not static. Instead, they are remodeled in response to changes in the prevailing physicochemical environment of the cell and as a result of intermolecular base pairing and interactions with RNA-binding proteins. Remarkable technical advances now allow us to probe RNA secondary structure at single-nucleotide resolution and genome-wide, both in vitro and in vivo...
November 23, 2016: Annual Review of Genetics
https://www.readbyqxmd.com/read/27572442/dynamics-of-the-human-and-viral-m-6-a-rna-methylomes-during-hiv-1-infection-of-t-cells
#14
Gianluigi Lichinchi, Shang Gao, Yogesh Saletore, Gwendolyn Michelle Gonzalez, Vikas Bansal, Yinsheng Wang, Christopher E Mason, Tariq M Rana
N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of eukaryotic mRNA. Very little is known of the function of m(6)A in the immune system or its role in host-pathogen interactions. Here, we investigate the topology, dynamics and bidirectional influences of the viral-host RNA methylomes during HIV-1 infection of human CD4 T cells. We show that viral infection triggers a massive increase in m(6)A in both host and viral mRNAs. In HIV-1 mRNA, we identified 14 methylation peaks in coding and noncoding regions, splicing junctions and splicing regulatory sequences...
2016: Nature Microbiology
https://www.readbyqxmd.com/read/27534815/biochemical-characterization-of-apobec3h-variants-implications-for-their-hiv-1-restriction-activity-and-mc-modification
#15
Jiang Gu, Qihan Chen, Xiao Xiao, Fumiaki Ito, Aaron Wolfe, Xiaojiang S Chen
APOBEC3H (A3H) is the most polymorphic member of the APOBEC3 family. Seven haplotypes (hap I-VII) and four mRNA splicing variants (SV) of A3H have been identified. The various haplotypes differ in anti-HIV activity, which is attributed to differences in protein stability, subcellular distribution, and/or RNA binding and virion packaging. Here, we report the first comparative biochemical studies of all the A3H variants using highly purified proteins. We show that all haplotypes were stably expressed and could be purified to homogeneity by Escherichia coli expression...
August 14, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27455303/a-phylogenetic-survey-on-the-structure-of-the-hiv-1-leader-rna-domain-that-encodes-the-splice-donor-signal
#16
Nancy Mueller, Atze T Das, Ben Berkhout
RNA splicing is a critical step in the human immunodeficiency virus type 1 (HIV-1) replication cycle because it controls the expression of the complex viral proteome. The major 5' splice site (5'ss) that is positioned in the untranslated leader of the HIV-1 RNA transcript is of particular interest because it is used for the production of the more than 40 differentially spliced subgenomic mRNAs. HIV-1 splicing needs to be balanced tightly to ensure the proper levels of all viral proteins, including the Gag-Pol proteins that are translated from the unspliced RNA...
2016: Viruses
https://www.readbyqxmd.com/read/27432972/defective-hiv-1-proviruses-produce-novel-protein-coding-rna-species-in-hiv-infected-patients-on-combination-antiretroviral-therapy
#17
Hiromi Imamichi, Robin L Dewar, Joseph W Adelsberger, Catherine A Rehm, Una O'Doherty, Ellen E Paxinos, Anthony S Fauci, H Clifford Lane
Despite years of plasma HIV-RNA levels <40 copies per milliliter during combination antiretroviral therapy (cART), the majority of HIV-infected patients exhibit persistent seropositivity to HIV-1 and evidence of immune activation. These patients also show persistence of proviruses of HIV-1 in circulating peripheral blood mononuclear cells. Many of these proviruses have been characterized as defective and thus thought to contribute little to HIV-1 pathogenesis. By combining 5'LTR-to-3'LTR single-genome amplification and direct amplicon sequencing, we have identified the presence of "defective" proviruses capable of transcribing novel unspliced HIV-RNA (usHIV-RNA) species in patients at all stages of HIV-1 infection...
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27355361/sequence-analysis-of-in-vivo-expressed-hiv-1-spliced-rnas-reveals-the-usage-of-new-and-unusual-splice-sites-by-viruses-of-different-subtypes
#18
Yolanda Vega, Elena Delgado, Jorge de la Barrera, Cristina Carrera, Ángel Zaballos, Isabel Cuesta, Ana Mariño, Antonio Ocampo, Celia Miralles, Sonia Pérez-Castro, Hortensia Álvarez, Isabel López-Miragaya, Elena García-Bodas, Francisco Díez-Fuertes, Michael M Thomson
HIV-1 RNAs are generated through a complex splicing mechanism, resulting in a great diversity of transcripts, which are classified in three major categories: unspliced, singly spliced (SS), and doubly spliced (DS). Knowledge on HIV-1 RNA splicing in vivo and by non-subtype B viruses is scarce. Here we analyze HIV-1 RNA splice site usage in CD4+CD25+ lymphocytes from HIV-1-infected individuals through pyrosequencing. HIV-1 DS and SS RNAs were amplified by RT-PCR in 19 and 12 samples, respectively. 13,108 sequences from HIV-1 spliced RNAs, derived from viruses of five subtypes (A, B, C, F, G), were identified...
2016: PloS One
https://www.readbyqxmd.com/read/27257867/pur-alpha-induces-jcv-gene-expression-and-viral-replication-by-suppressing-srsf1-in-glial-cells
#19
Ilker Kudret Sariyer, Rahsan Sariyer, Jessica Otte, Jennifer Gordon
OBJECTIVE: PML is a rare and fatal demyelinating disease of the CNS caused by the human polyomavirus, JC virus (JCV), which occurs in AIDS patients and those on immunosuppressive monoclonal antibody therapies (mAbs). We sought to identify mechanisms that could stimulate reactivation of JCV in a cell culture model system and targeted pathways which could affect early gene transcription and JCV T-antigen production, which are key steps of the viral life cycle for blocking reactivation of JCV...
2016: PloS One
https://www.readbyqxmd.com/read/27173921/viruses-mark-thy-message-well
#20
Fengchun Ye, Jonathan Karn
Post-transcriptional m(6)A methylation of RNA has profound effects on RNA splicing, export, stability, and translation. A recent study by Lichinchi et al. (2016) and one in this issue of Cell Host & Microbe by Kennedy et al. (2016) demonstrate that HIV mRNA is extensively m(6)A methylated, which promotes efficient virus replication.
May 11, 2016: Cell Host & Microbe
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