The C-Terminal Tail of the Gp41 Transmembrane Envelope
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HIV-1 Rev Downregulates Tat Expression and Viral Replication Via Modulation of NAD(P)H:Quinine Oxidoreductase 1 (NQO1)
ARTICLE Received 25 Jul 2014 | Accepted 22 Apr 2015 | Published 10 Jun 2015 DOI: 10.1038/ncomms8244 HIV-1 Rev downregulates Tat expression and viral replication via modulation of NAD(P)H:quinine oxidoreductase 1 (NQO1) Sneh Lata1,*, Amjad Ali2,*, Vikas Sood1,2,w, Rameez Raja2 & Akhil C. Banerjea2 HIV-1 gene expression and replication largely depend on the regulatory proteins Tat and Rev, but it is unclear how the intracellular levels of these viral proteins are regulated after infection. Here we report that HIV-1 Rev causes specific degradation of cytoplasmic Tat, which results in inhibition of HIV-1 replication. The nuclear export signal (NES) region of Rev is crucial for this activity but is not involved in direct interactions with Tat. Rev reduces the levels of ubiquitinated forms of Tat, which have previously been reported to be important for its transcriptional properties. Tat is stabilized in the presence of NAD(P)H:quinine oxidoreductase 1 (NQO1), and potent degradation of Tat is induced by dicoumarol, an NQO1 inhibitor. Furthermore, Rev causes specific reduction in the levels of endogenous NQO1. Thus, we propose that Rev is able to induce degradation of Tat indirectly by downregulating NQO1 levels. Our findings have implications in HIV-1 gene expression and latency. 1 Department of Microbiology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi 110095, India. 2 Laboratory of Virology, National Institute of Immunology, New Delhi 110067, India. * These authors contributed equally to this work. w Present address: Translational Health Science and Technology Institute, Faridabad, Haryana 121004, India. Correspondence and requests for materials should be addressed to A.C.B. -
Symposium on Viral Membrane Proteins
Viral Membrane Proteins ‐ Shanghai 2011 交叉学科论坛 Symposium for Advanced Studies 第二十七期:病毒离子通道蛋白的结构与功能研讨会 Symposium on Viral Membrane Proteins 主办单位:中国科学院上海交叉学科研究中心 承办单位:上海巴斯德研究所 1 Viral Membrane Proteins ‐ Shanghai 2011 Symposium on Viral Membrane Proteins Shanghai Institute for Advanced Studies, CAS Institut Pasteur of Shanghai,CAS 30.11. – 2.12 2011 Shanghai, China 2 Viral Membrane Proteins ‐ Shanghai 2011 Schedule: Wednesday, 30th of November 2011 Morning Arrival Thursday, 1st of December 2011 8:00 Arrival 9:00 Welcome Bing Sun, Co-Director, Pasteur Institute Shanghai 9: 10 – 9:35 Bing Sun, Pasteur Institute Shanghai Ion channel study and drug target fuction research of coronavirus 3a like protein. 9:35 – 10:00 Tim Cross, Tallahassee, USA The proton conducting mechanism and structure of M2 proton channel in lipid bilayers. 10:00 – 10:25 Shy Arkin, Jerusalem, IL A backbone structure of SARS Coronavirus E protein based on Isotope edited FTIR, X-ray reflectivity and biochemical analysis. 10:20 – 10:45 Coffee Break 10:45 – 11:10 Rainer Fink, Heidelberg, DE Elektromechanical coupling in muscle: a viral target? 11:10 – 11:35 Yechiel Shai, Rehovot, IL The interplay between HIV1 fusion peptide, the transmembrane domain and the T-cell receptor in immunosuppression. 11:35 – 12:00 Christoph Cremer, Mainz and Heidelberg University, DE Super-resolution Fluorescence imaging of cellular and viral nanostructures. 12:00 – 13:30 Lunch Break 3 Viral Membrane Proteins ‐ Shanghai 2011 13:30 – 13:55 Jung-Hsin Lin, National Taiwan University Robust Scoring Functions for Protein-Ligand Interactions with Quantum Chemical Charge Models. 13:55 – 14:20 Martin Ulmschneider, Irvine, USA Towards in-silico assembly of viral channels: the trials and tribulations of Influenza M2 tetramerization. -
Viroporins: Structures and Functions Beyond Cell Membrane Permeabilization
Editorial Viroporins: Structures and Functions beyond Cell Membrane Permeabilization José Luis Nieva 1,* and Luis Carrasco 2,* Received: 17 September 2015 ; Accepted: 21 September 2015 ; Published: 29 September 2015 Academic Editor: Eric O. Freed 1 Biophysics Unit (CSIC, UPV/EHU) and Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain 2 Centro de Biología Molecular Severo Ochoa (CSIC, UAM), c/Nicolás Cabrera, 1, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain * Correspondence: [email protected] (J.L.N.); [email protected] (L.C.); Tel.: +34-94-601-3353 (J.L.N.); +34-91-497-8450 (L.C.) Viroporins represent an interesting group of viral proteins that exhibit two sets of functions. First, they participate in several viral processes that are necessary for efficient production of virus progeny. Besides, viroporins interfere with a number of cellular functions, thus contributing to viral cytopathogenicity. Twenty years have elapsed from the first review on viroporins [1]; since then several reviews have covered the advances on viroporin structure and functioning [2–8]. This Special Issue updates and revises new emerging roles of viroporins, highlighting their potential use as antiviral targets and in vaccine development. Viroporin structure. Viroporins are usually short proteins with at least one hydrophobic amphipathic helix. Homo-oligomerization is achieved by helix–helix interactions in membranes rendering higher order structures, forming aqueous pores. Progress in viroporin structures during the last 2–3 years has in some instances provided a detailed knowledge of their functional architecture, including the fine definition of binding sites for effective inhibitors. -
Opportunistic Intruders: How Viruses Orchestrate ER Functions to Infect Cells
REVIEWS Opportunistic intruders: how viruses orchestrate ER functions to infect cells Madhu Sudhan Ravindran*, Parikshit Bagchi*, Corey Nathaniel Cunningham and Billy Tsai Abstract | Viruses subvert the functions of their host cells to replicate and form new viral progeny. The endoplasmic reticulum (ER) has been identified as a central organelle that governs the intracellular interplay between viruses and hosts. In this Review, we analyse how viruses from vastly different families converge on this unique intracellular organelle during infection, co‑opting some of the endogenous functions of the ER to promote distinct steps of the viral life cycle from entry and replication to assembly and egress. The ER can act as the common denominator during infection for diverse virus families, thereby providing a shared principle that underlies the apparent complexity of relationships between viruses and host cells. As a plethora of information illuminating the molecular and cellular basis of virus–ER interactions has become available, these insights may lead to the development of crucial therapeutic agents. Morphogenesis Viruses have evolved sophisticated strategies to establish The ER is a membranous system consisting of the The process by which a virus infection. Some viruses bind to cellular receptors and outer nuclear envelope that is contiguous with an intri‑ particle changes its shape and initiate entry, whereas others hijack cellular factors that cate network of tubules and sheets1, which are shaped by structure. disassemble the virus particle to facilitate entry. After resident factors in the ER2–4. The morphology of the ER SEC61 translocation delivering the viral genetic material into the host cell and is highly dynamic and experiences constant structural channel the translation of the viral genes, the resulting proteins rearrangements, enabling the ER to carry out a myriad An endoplasmic reticulum either become part of a new virus particle (or particles) of functions5. -
Human Retroviruses in the Second Decade: a Personal Perspective
© 1995 Nature Publishing Group http://www.nature.com/naturemedicine • REVIEW Human retroviruses in the second decade: A personal perspective Human retroviruses have developed novel strategies for their propagation and survival. A consequence of their success has been the induction of an extraordinarily diverse set of human dlst!ases, including AIDS, cancers and neurological and Inflammatory disorders. Early research focused on their characterization, linkage to these dlst!ases, and the mechanisms Involved. Research should now aim at the eradication of human retroviruses and on treatment of infected people. Retroviruses are transmitted either geneti- .................... ···.. .... ·. ..... .. discovered". Though its characteristics are cally (endogenous form) or as infectious ROBERT C. GALLO strikingly similar to HTLV-1, HTLV-II is not agents (exogenous form)'·'. As do many so clearly linked to human disease. It is cu other animal species, humans have both forms ..... In general, rious that HTLV-11 is endemic in some American Indians and endogenous retroviruses are evolutionary relics of old infec more prevalent in drug addicts than HTLV-I"·'•. tions and are not known to cause disease. The DNA of many HIV-1 is also most prevalent in equatorial Africa, but in con species, including humans, harbours multiple copies of differ trast to HTLV the demography of the HIV epidemic is still in ent retroviral proviruses. The human endogenous proviral flux, and the virus is new to most of the world. The number of sequences are virtually all defective, and comprise about one infected people worldwide is now estimated to be about 17 mil percent of the human genome, though R. Kurth's group in lion and is predicted to reach 30 to SO million by the year 2000. -
Mechanisms of Action of Novel Influenza A/M2 Viroporin Inhibitors Derived from Hexamethylene Amiloride S
Supplemental material to this article can be found at: http://molpharm.aspetjournals.org/content/suppl/2016/05/18/mol.115.102731.DC1 1521-0111/90/2/80–95$25.00 http://dx.doi.org/10.1124/mol.115.102731 MOLECULAR PHARMACOLOGY Mol Pharmacol 90:80–95, August 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Mechanisms of Action of Novel Influenza A/M2 Viroporin Inhibitors Derived from Hexamethylene Amiloride s Pouria H. Jalily, Jodene Eldstrom, Scott C. Miller, Daniel C. Kwan, Sheldon S. -H. Tai, Doug Chou, Masahiro Niikura, Ian Tietjen, and David Fedida Department of Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver (P.H.J., J.E., S.C.M., D.C.K., D.C., I.T., D.F.), and Faculty of Health Sciences, Simon Fraser University, Burnaby (S.S.-H.T., M.N., I.T.), British Columbia, Canada Received December 7, 2015; accepted May 12, 2016 Downloaded from ABSTRACT The increasing prevalence of influenza viruses with resistance to [1,19-biphenyl]-4-carboxylate (27) acts both on adamantane- approved antivirals highlights the need for new anti-influenza sensitive and a resistant M2 variant encoding a serine to asparagine therapeutics. Here we describe the functional properties of hexam- 31 mutation (S31N) with improved efficacy over amantadine and – 5 m m ethylene amiloride (HMA) derived compounds that inhibit the wild- HMA (IC50 0.6 Mand4.4 M, respectively). Whereas 9 inhibited molpharm.aspetjournals.org type and adamantane-resistant forms of the influenza A M2 ion in vitro replication of influenza virus encoding wild-type M2 (EC50 5 channel. -
Filoviral Immune Evasion Mechanisms
Viruses 2011, 3, 1634-1649; doi:10.3390/v3091634 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review Filoviral Immune Evasion Mechanisms Parameshwaran Ramanan 1,3, Reed S. Shabman 2, Craig S. Brown 1,4, Gaya K. Amarasinghe 1,*, Christopher F. Basler 2,* and Daisy W. Leung 1,* 1 Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, USA 2 Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA 3 Biochemistry Graduate Program, Iowa State University, Ames, IA 50011, USA 4 Biochemistry Undergraduate Program, Iowa State University, Ames, IA 50011, USA * Authors to whom correspondence should be addressed; [email protected] (G.K.A); [email protected] (C.F.B); [email protected] (D.W.L.). Received: 11 August 2011 / Accepted: 15 August 2011 / Published: 7 September 2011 Abstract: The Filoviridae family of viruses, which includes the genera Ebolavirus (EBOV) and Marburgvirus (MARV), causes severe and often times lethal hemorrhagic fever in humans. Filoviral infections are associated with ineffective innate antiviral responses as a result of virally encoded immune antagonists, which render the host incapable of mounting effective innate or adaptive immune responses. The Type I interferon (IFN) response is critical for establishing an antiviral state in the host cell and subsequent activation of the adaptive immune responses. Several filoviral encoded components target Type I IFN responses, and this innate immune suppression is important for viral replication and pathogenesis. For example, EBOV VP35 inhibits the phosphorylation of IRF-3/7 by the TBK-1/IKKε kinases in addition to sequestering viral RNA from detection by RIG-I like receptors. -
A Novel Ebola Virus VP40 Matrix Protein-Based Screening for Identification of Novel Candidate Medical Countermeasures
viruses Communication A Novel Ebola Virus VP40 Matrix Protein-Based Screening for Identification of Novel Candidate Medical Countermeasures Ryan P. Bennett 1,† , Courtney L. Finch 2,† , Elena N. Postnikova 2 , Ryan A. Stewart 1, Yingyun Cai 2 , Shuiqing Yu 2 , Janie Liang 2, Julie Dyall 2 , Jason D. Salter 1 , Harold C. Smith 1,* and Jens H. Kuhn 2,* 1 OyaGen, Inc., 77 Ridgeland Road, Rochester, NY 14623, USA; [email protected] (R.P.B.); [email protected] (R.A.S.); [email protected] (J.D.S.) 2 NIH/NIAID/DCR/Integrated Research Facility at Fort Detrick (IRF-Frederick), Frederick, MD 21702, USA; courtney.fi[email protected] (C.L.F.); [email protected] (E.N.P.); [email protected] (Y.C.); [email protected] (S.Y.); [email protected] (J.L.); [email protected] (J.D.) * Correspondence: [email protected] (H.C.S.); [email protected] (J.H.K.); Tel.: +1-585-697-4351 (H.C.S.); +1-301-631-7245 (J.H.K.) † These authors contributed equally to this work. Abstract: Filoviruses, such as Ebola virus and Marburg virus, are of significant human health concern. From 2013 to 2016, Ebola virus caused 11,323 fatalities in Western Africa. Since 2018, two Ebola virus disease outbreaks in the Democratic Republic of the Congo resulted in 2354 fatalities. Although there is progress in medical countermeasure (MCM) development (in particular, vaccines and antibody- based therapeutics), the need for efficacious small-molecule therapeutics remains unmet. Here we describe a novel high-throughput screening assay to identify inhibitors of Ebola virus VP40 matrix protein association with viral particle assembly sites on the interior of the host cell plasma membrane. -
Inhibition of Tat-Mediated Transactivation and HIV Replication with Tat Mutant and Repressor Domain Fusion Proteins
Gene Therapy (1998) 5, 946–954 1998 Stockton Press All rights reserved 0969-7128/98 $12.00 http://www.stockton-press.co.uk/gt Inhibition of Tat-mediated transactivation and HIV replication with Tat mutant and repressor domain fusion proteins C Fraisier1,2, DA Abraham1, M van Oijen1, V Cunliffe3, A Irvine3, R Craig3 and EA Dzierzak1,2 1National Institute for Medical Research, Division of Eukaryotic Molecular Genetics, London, UK; 2Erasmus University Rotterdam, Department of Cell Biology and Genetics, Rotterdam, The Netherlands; and 3Therexsys Ltd, The Science Park, University of Keele, Keele, UK Strategies to inhibit the spread of HIV infection consist of moter. This fusion mutant was also examined for its a number of specific molecular approaches. Since viral capacity to block both Tat-mediated transactivation and production is dependent upon Tat-mediated transactivation HIV replication. We show that three mutants Tat⌬53, of the HIV promoter through the Tat activating region Tat⌬58 and Tat⌬53/Eng result in a transdominant pheno- (TAR), tat antisense RNA, anti-tat ribozymes, TAR decoys type inhibiting wild-type Tat-mediated transactivation, and and dominant negative Tat mutant proteins have been sug- that the inhibiting potential is increased by the presence of gested as therapeutic inhibitors. We produced and tested the entire basic domain or the fusion of a repressor several Tat mutant proteins, including a newly generated domain. However, only the transdominant mutants Tat⌬58 form Tat⌬58, for the ability to inhibit Tat-mediated trans- and Tat⌬53/Eng significantly inhibit HIV-1 replication after activation and HIV production. In addition, we generated a infection of transfected T cell lines. -
Functional Control of HIV-1 Post-Transcriptional Gene Expression by Host Cell Factors
Functional control of HIV-1 post-transcriptional gene expression by host cell factors DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Amit Sharma, B.Tech. Graduate Program in Molecular Genetics The Ohio State University 2012 Dissertation Committee Dr. Kathleen Boris-Lawrie, Advisor Dr. Anita Hopper Dr. Karin Musier-Forsyth Dr. Stephen Osmani Copyright by Amit Sharma 2012 Abstract Retroviruses are etiological agents of several human and animal immunosuppressive disorders. They are associated with certain types of cancer and are useful tools for gene transfer applications. All retroviruses encode a single primary transcript that encodes a complex proteome. The RNA genome is reverse transcribed into DNA, integrated into the host genome, and uses host cell factors to transcribe, process and traffic transcripts that encode viral proteins and act as virion precursor RNA, which is packaged into the progeny virions. The functionality of retroviral RNA is governed by ribonucleoprotein (RNP) complexes formed by host RNA helicases and other RNA- binding proteins. The 5’ leader of retroviral RNA undergoes alternative inter- and intra- molecular RNA-RNA and RNA-protein interactions to complete multiple steps of the viral life cycle. Retroviruses do not encode any RNA helicases and are dependent on host enzymes and RNA chaperones. Several members of the host RNA helicase superfamily are necessary for progressive steps during the retroviral replication. RNA helicase A (RHA) interacts with the redundant structural elements in the 5’ untranslated region (UTR) of retroviral and selected cellular mRNAs and this interaction is necessary to facilitate polyribosome formation and productive protein synthesis. -
Feline Origin of Rotavirus Strain, Tunisia
Article DOI: http://dx.doi.org/10.3201/eid1904.121383 Feline Origin of Rotavirus Strain, Tunisia Technical Appendix Table 1. Primers used for amplification and sequencing of the whole genome of group A rotavirus strain RVA/human-wt/TUN/17237/2008/G6P[9] from Tunisia, 2008 Gene Primer name Primer sequence VP1 Gen_VP1Fb 5 -GGC TAT TAA AGC TRT ACA ATG GGG AAG -3 Gen_VP1Rb 5 -GGT CAC ATC TAA GCG YTC TAA TCT TG -3 MG6_VP1_447F 5 -TGC AGT TAT GTT CTG GTT GG -3 Hosokawa_VP1_2587R 5 -ACG CTG ATA TTT GCG CAC -3 LAP_VP1_1200F 5 -GCT GTC AAT GTC ATC AGC -3 Gen_VP1_2417R 5 -GCT ATY TCA TCA GCT ATT CCY G -3 30-96_VP1_3163F 5 -GGA TCA TGG ATA AGC TTG TTC TG -3 26097_VP1_269R 5 -GCG TTA TAC TTA TCA TAC GAA TAC G -3 VP2 Gen_VP2Fc 5 -GGC TAT TAA AGG YTC AAT GGC GTA CAG -3 Gen_VP2Rbc 5 -GTC ATA TCT CCA CAR TGG GGT TGG -3 26097_VP2_458F 5 -AGT TGC GTA ATA GAT GGT ATT GG -3 B1711_VP2_2112R 5 -GCA ATT TTA TCT GAG GCA CG -3 NCDV_VP2_1868F 5 -AGG ATT AAT GAT GCA GTG GC -3 LAP_VP2_2543F 5 -GAC ATC AAA TCT TAC CTT CAC TG -3 260-97_VP2_345R 5 -GAC TCT TTT GGT TCG AAA GTA GG -3 FR5_VP2_23F 5 -TAC AGG AAA CGT GGA GCG -3 260-97_VP2_744R 5 -GTACTCTTTGTCTCATTTCCGC -3 Gen_VP2_2739Ra 5 -TAC AAC TCG TTC ATG ATG CG -3 VP3 Gen_VP3_24F 5 -TGY GTT TTA CCT CTG ATG GTG-3 Gen_VP3_2584R 5 -TGA CYA GTG TGT TAA GTT TYT AGC-3 NCDV_VP3_2026R 5 -CAT GCG TAA ATC AAC TCT ATC GG -3 MG6_VP3_488F 5 -GCA GCT ACA GAT GATGAT GC -3 B10925_VP3_2416F 5 -ACA ATC GAG AAT GTT CAT CCC -3 TUN1_VP3_167R 5 -TTT CTA CTG CAG CTA TGC CAG-3 VP4 LAP_VP4_788F 5 -CCT TGT GGA AAG AAA TGC-3 VP4_2348-2368Re 5 -
Lentivirus and Lentiviral Vectors Fact Sheet
Lentivirus and Lentiviral Vectors Family: Retroviridae Genus: Lentivirus Enveloped Size: ~ 80 - 120 nm in diameter Genome: Two copies of positive-sense ssRNA inside a conical capsid Risk Group: 2 Lentivirus Characteristics Lentivirus (lente-, latin for “slow”) is a group of retroviruses characterized for a long incubation period. They are classified into five serogroups according to the vertebrate hosts they infect: bovine, equine, feline, ovine/caprine and primate. Some examples of lentiviruses are Human (HIV), Simian (SIV) and Feline (FIV) Immunodeficiency Viruses. Lentiviruses can deliver large amounts of genetic information into the DNA of host cells and can integrate in both dividing and non- dividing cells. The viral genome is passed onto daughter cells during division, making it one of the most efficient gene delivery vectors. Most lentiviral vectors are based on the Human Immunodeficiency Virus (HIV), which will be used as a model of lentiviral vector in this fact sheet. Structure of the HIV Virus The structure of HIV is different from that of other retroviruses. HIV is roughly spherical with a diameter of ~120 nm. HIV is composed of two copies of positive ssRNA that code for nine genes enclosed by a conical capsid containing 2,000 copies of the p24 protein. The ssRNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the development of the virion: reverse transcriptase (RT), proteases (PR), ribonuclease and integrase (IN). A matrix composed of p17 surrounds the capsid ensuring the integrity of the virion. This, in turn, is surrounded by an envelope composed of two layers of phospholipids taken from the membrane of a human cell when a newly formed virus particle buds from the cell.