DOCSLIB.ORG

Retroviruses:Retroviruses: Endogenousendogenous MLVMLV Andand XMRVXMRV

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Retroviruses:Retroviruses: Endogenousendogenous MLVMLV Andand XMRVXMRV Retroviruses:Retroviruses: EndogenousEndogenous MLVMLV andand XMRVXMRV JohnJohn M.M. CoffinCoffin TuftsTufts UniversityUniversity Tufts University Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA The Retrovirus Family Tree Virus Genus HFV Spumaretrovirinae bel1, bel2 MLV GammaretrovirusGammaretroviru FeLV HERV-C WDS Epsilonretrovirus orfA, orfB, orfC HIV-1 tat, rev HIV-2 Lentivirus EIAV VMV dut MPMV sag new env MMTV Betaretrovirus HERV-K IAP ASLV Alpharetrovirus BLV HTLV-1 Deltaretrovirus tax, rex HTLV-2 New Genes Presented at the 1st Intl. Workshop on XMRV At least 30 million years ago! 7-8 September, Bethesda USA EndogenousEndogenous RetrovirusesRetroviruses 1.1. Remnants Remnants ofof germgerm lineline infectionsinfections byby exogenousexogenous (infectious)(infectious) retroviruses.retroviruses. 2.2. BecameBecame fixedfixed inin thethe hosthost speciespecies.Somes.Some conferconfer protectionprotection againstagainst futurefuture infectionsinfections byby thethe samesame oror similarsimilar viviruses.ruses. AA fewfew othersothers havehave salutarysalutary effects.effects. 3.3. InheritedInherited likelike normalnormal genes.genes. 4.4. PresentPresent inin everyevery vertebratevertebrate andand manymany invertebrates.invertebrates. 5.5. CompriseComprise 6-8%6-8% ofof thethe humanhuman genome.genome. (More(More virusesviruses thanthan us).us). Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA EndogenousEndogenous RetrovirusesRetroviruses 6. Provide a fossil record of pathogen-host interactioninteraction unavailableunavailable inin anyany other system. 7. Can participateparticipate in evolutionary processescesses asas wellwell asas informinform usus aboutabout them. 8. Involved in disease in some animals. Humans? Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA XMRVXMRV 1.1. First First describeddescribed aboutabout 55 yearsyears agoago inin aa fewfew patientspatients withwith prostateprostate cancer.cancer. 2.2. Within Within thethe lastlast year:year: •• Reported Reported inin 25%25% ofof prostateprostate cancercancer biopsies.biopsies. •• Reported Reported inin 67%67% ofof chronicchronic fatiguefatigue syndromesyndrome patients.patients. •• Reported Reported inin 4%4% ofof normalnormal controlscontrols inin bothboth studies.studies. •• Not Not alwaysalways foundfound inin studiesstudies fromfrom otherother labslabs onon samplessamples fromfrom eithereither disease.disease. 3.3. Isolates Isolates fromfrom thethe 22 diseasesdiseases atat didifferentfferent timestimes andand locationslocations areare almostalmost identicalidentical toto oneone another.another. 4.4. Causality, Causality, prevalence,prevalence, andand distridistributionbution remainremain toto bebe established.established. 5.5. Very Very closelyclosely relatedrelated toto endogenousendogenous xenotropicxenotropic (X)(X) MLV.MLV. 6.6. Recently, Recently, LoLo etet alal (PNAS)(PNAS) reportereportedd alsoalso findingfinding MLV-likeMLV-like (PMV(PMV andand MPMVMPMV related)related) virusvirus sequencessequences associatedassociated withwith CFS.CFS. Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA GammaretrovirusesGammaretroviruses 1.1. Simple Simple retrovirusesretroviruses (only(only gag,gag, polpol,, andand envenv genes).genes). 2.2. Widespread Widespread inin nature,nature, withwith isolatesisolates fromfrom mammalsmammals (mice,(mice, cats,cats, primates,primates, koalaskoalas andand others),others), birds,birds, andand reptiles.reptiles. 3.3. Readily Readily givegive riserise toto endogenousendogenous proviruses.proviruses. 4.4. Most Most commonlycommonly transmittedtransmitted verticallyvertically (mother(mother toto offspring).offspring). 5.5. Cause Cause aa widewide varietyvariety ofof diseasesdiseases (cancer,(cancer, neurological,neurological, degenerative,degenerative, immunodeficiency).immunodeficiency). 6.6. Cancer Cancer isis usuallyusually thethe resultresult ofof insinsertionalertional inactivationinactivation ofof protooncogenes.protooncogenes. 7.7. Infection Infection isis lifelong,lifelong, withwith persistencepersistence ofof infectedinfected cellscells establishedestablished early,early, and-and- unlikeunlike HIV,HIV, veryvery fewfew replreplicationication cyclescycles perper host.host. Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA XenotropicXenotropic MLVMLV 1.1. InheritedInherited asas endogenousendogenous provirprovirusesuses (ca(ca 10-2010-20 copies)copies) in all inbred mice. 2.2. Many Many moremore provirusesproviruses inin somesome wildwild MusMus MusculusMusculus subsubspecies.species. 3.3. SomeSome provirusesproviruses (e.g., Bxv1-XMV43)MV43) areare intactintact andand infectious.infectious. 4.4. Can Can infectinfect virtuallyvirtually allall mammals,mammals, exceptexcept somesome speciesspecies ofof MusMus,, duedue toto receptorreceptor (Xpr1)(Xpr1) polymorphism.polymorphism. 5.5. Not Not directlydirectly pathogenicpathogenic inin micemice (due(due toto lacklack ofof receptor),receptor), butbut LTRLTR isis oftenoften foundfound inin oncogeniconcogenic recombinantrecombinant MLVs.MLVs. 6.6. Pathogenicity Pathogenicity inin otherother speciesspecies isis unknown.unknown. 7.7. Common Common contaminantcontaminant ofof humanhuman tumortumor cellcell lineslines duedue toto passagepassage throughthrough nudenude micemice (which(which havehave Bxv1).Bxv1). 8.8. Closely Closely relatedrelated toto XMRV,XMRV, butbut nonenone isis identical,identical, perhapsperhaps excludingexcluding inbredinbred micemice asas thethe origin.origin. 9.9. Related Related MLVsMLVs causecause aa widewide varietyvariety ofof diseasesdiseases (malignant,(malignant, immunodeficiency,immunodeficiency, neurological)neurological) inin mice.mice. Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA PolytropicPolytropic andand ModifiedModified PolytropicPolytropic MLVMLV 1.1. InheritedInherited asas endogenousendogenous provirprovirusesuses (ca(ca 10-2010-20 copiescopies each)each) inin allall inbredinbred mice.mice. 2.2. Also Also foundfound inin wildwild MusMus MusculusMusculus subsubspecies.species. 3.3. NoNo infectiousinfectious virusvirus hashas beenbeen foundfound toto date.date. 4.4. Can Can infectinfect virtuallyvirtually allall mammals,mammals, ususinging bothboth forms of the Xpr1 Receptor. 5.5. Not Not directlydirectly pathogenicpathogenic inin micemice ((duedue toto lacklack ofof infectivity?),infectivity?), butbut envenv genegene isis oftenoften foundfound inin oncogeniconcogenic recombinantrecombinant MLVs.MLVs. 6.6. Pathogenicity Pathogenicity inin otherother speciesspecies isis unknown.unknown. 7.7. Both Both typestypes derivedderived independentlyindependently fromfrom XMV,XMV, probablyprobably inin responseresponse toto Xpr1Xpr1 mutation.mutation. 8.8. Unlike Unlike XMV,XMV, PMVPMV andand MPMVMPMV provprovirusesiruses havehave sufferedsuffered significantsignificant mutationsmutations mediatedmediated byby mousemouse APOBEC3.APOBEC3. Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA Formation of Endogenous Proviruses Long terminal repeats (LTR’s) provirus Identical sequence st Endogenous provirus Presented at the 1 Intl. Workshop on XMRV 7-8 September, Bethesda USA Host-Retrovirus Evolution Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA Effects of Endogenous Proviruses (Good and Bad) Syncytin env Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA Four Classes of Endogenous MLV BHBB B Ecotropic pEco BBBE Xenotropic js6/10 BB B E Polytropic js5 BB H B E Modified polytropic js4 Selective hybridization probe Insert in LTR Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA Detection of Specific Proviruses Specific restriction sites Probe Specific hybridization probe A B Size of fragments detected depends on location of cleavage site in flanking DNA, one band per provirus. Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA Distribution of Endogenous Proviruses in Inbred Mice B C Ak D H A L B H Ak D A L C B C Ak D H A L PmvMpmv Xmv Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA Distribution of Endogenous MLV’s on Mouse Chromosomes 12345678910 =10cM =centromere =Emv =Pmv =Mpmv =Xmv =Mtv =Pltr =Mltr =Xltr 11 12 13 14 15 16 17 18 19 X Y Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA OncogenesisOncogenesis byby EndogenousEndogenous MLVMLV 1.1. In In AKRAKR andand somesome otherother inbredinbred strains,strains, mostmost micemice diedie withinwithin aa yearyear ofof thymicthymic lymphoma.lymphoma. 2.2. The The proximalproximal causecause isis integrationintegration adjacentadjacent toto oneone oror moremore protooncogenesprotooncogenes ((c-mycc-myc,, pim-1pim-1,, andand others)others) ofof aa provirusprovirus derivedderived fromfrom endogenousendogenous MLV.MLV. 3.3. Around Around thethe timetime ofof birthbirth allall micemice expressexpress aa replicatingreplicating ecotropicecotropic virusvirus (AKV).(AKV). 4.4. A A complex,complex, butbut highlyhighly reproduciblereproducible seriserieses ofof eventsevents leadsleads toto thethe formation formation ofof aa recombinantrecombinant virusvirus containingcontaining aa polytropicpolytropic envenv genegene andand anan LTRLTR derivedderived fromfrom bxv1bxv1 andand modifiedmodified byby enhancerenhancer duplicationduplication.. Presented at the 1st Intl. Workshop on XMRV 7-8 September, Bethesda USA Generation and selection
Load more

Recommended publications
  • Non-Primate Lentiviral Vectors and Their Applications in Gene Therapy for Ocular Disorders
    viruses Review Non-Primate Lentiviral Vectors and Their Applications in Gene Therapy for Ocular Disorders Vincenzo Cavalieri 1,2,* ID , Elena Baiamonte 3 and Melania Lo Iacono 3 1 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze Edificio 16, 90128 Palermo, Italy 2 Advanced Technologies Network (ATeN) Center, University of Palermo, Viale delle Scienze Edificio 18, 90128 Palermo, Italy 3 Campus of Haematology Franco e Piera Cutino, Villa Sofia-Cervello Hospital, 90146 Palermo, Italy; [email protected] (E.B.); [email protected] (M.L.I.) * Correspondence: [email protected] Received: 30 April 2018; Accepted: 7 June 2018; Published: 9 June 2018 Abstract: Lentiviruses have a number of molecular features in common, starting with the ability to integrate their genetic material into the genome of non-dividing infected cells. A peculiar property of non-primate lentiviruses consists in their incapability to infect and induce diseases in humans, thus providing the main rationale for deriving biologically safe lentiviral vectors for gene therapy applications. In this review, we first give an overview of non-primate lentiviruses, highlighting their common and distinctive molecular characteristics together with key concepts in the molecular biology of lentiviruses. We next examine the bioengineering strategies leading to the conversion of lentiviruses into recombinant lentiviral vectors, discussing their potential clinical applications in ophthalmological research. Finally, we highlight the invaluable role of animal organisms, including the emerging zebrafish model, in ocular gene therapy based on non-primate lentiviral vectors and in ophthalmology research and vision science in general. Keywords: FIV; EIAV; BIV; JDV; VMV; CAEV; lentiviral vector; gene therapy; ophthalmology; zebrafish 1.
    [Show full text]
  • Guide for Common Viral Diseases of Animals in Louisiana
    Sampling and Testing Guide for Common Viral Diseases of Animals in Louisiana Please click on the species of interest: Cattle Deer and Small Ruminants The Louisiana Animal Swine Disease Diagnostic Horses Laboratory Dogs A service unit of the LSU School of Veterinary Medicine Adapted from Murphy, F.A., et al, Veterinary Virology, 3rd ed. Cats Academic Press, 1999. Compiled by Rob Poston Multi-species: Rabiesvirus DCN LADDL Guide for Common Viral Diseases v. B2 1 Cattle Please click on the principle system involvement Generalized viral diseases Respiratory viral diseases Enteric viral diseases Reproductive/neonatal viral diseases Viral infections affecting the skin Back to the Beginning DCN LADDL Guide for Common Viral Diseases v. B2 2 Deer and Small Ruminants Please click on the principle system involvement Generalized viral disease Respiratory viral disease Enteric viral diseases Reproductive/neonatal viral diseases Viral infections affecting the skin Back to the Beginning DCN LADDL Guide for Common Viral Diseases v. B2 3 Swine Please click on the principle system involvement Generalized viral diseases Respiratory viral diseases Enteric viral diseases Reproductive/neonatal viral diseases Viral infections affecting the skin Back to the Beginning DCN LADDL Guide for Common Viral Diseases v. B2 4 Horses Please click on the principle system involvement Generalized viral diseases Neurological viral diseases Respiratory viral diseases Enteric viral diseases Abortifacient/neonatal viral diseases Viral infections affecting the skin Back to the Beginning DCN LADDL Guide for Common Viral Diseases v. B2 5 Dogs Please click on the principle system involvement Generalized viral diseases Respiratory viral diseases Enteric viral diseases Reproductive/neonatal viral diseases Back to the Beginning DCN LADDL Guide for Common Viral Diseases v.
    [Show full text]
  • LENTIVIRUS and LENTIVIRAL VECTORS
    LENTIVIRUS and LENTIVIRAL VECTORS Risk Group: 3 I. Background and Health Hazards Lentiviruses are a subset of retroviruses that have the ability to integrate into host chromosomes and to infect non-dividing cells, and include human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) which can infect humans. Another commonly used lentivirus that is infectious to animals, but not humans, is feline immunodeficiency virus (FIV). Lentiviral vectors consist of recombinant or synthetic nucleic acid sequences and HIV or other lentivirus- based viral packaging and regulatory sequences flanked by either wild-type or chimeric long terminal repeat (LTR) regions. Use of these vector systems is particularly desirable because of their ability to integrate transgenes into dividing, as well as, non-dividing cells. However, there are risks associated with working with lentiviral vectors and these must be carefully evaluated. The two major risks are: 1) the potential generation of replication competent lentivirus (RCL); and 2) the potential for oncogenesis. These risks are largely based upon the vector system used and the transgene insert encoded by the vector. Therefore, it is imperative that prior to utilizing a lentiviral vector system, a risk assessment must be reviewed and documented. Also, because construction and/or use of lentiviral vectors falls under the definition of r/sNA research as outlined in the NIH Guidelines, possession must be reported in the workplace’s biological agent inventory and experiments must be submitted for review and approval by the site IBC prior to initiation. II. MODES OF TRANSMISSION Lentivirus is transmissible through injection, ingestion, exposure to broken skin or contact with mucous membranes of the eyes, nose and mouth.
    [Show full text]
  • The Expression of Human Endogenous Retroviruses Is Modulated by the Tat Protein of HIV‐1
    The Expression of Human Endogenous Retroviruses is modulated by the Tat protein of HIV‐1 by Marta Jeannette Gonzalez‐Hernandez A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Immunology) in The University of Michigan 2012 Doctoral Committee Professor David M. Markovitz, Chair Professor Gary Huffnagle Professor Michael J. Imperiale Associate Professor David J. Miller Assistant Professor Akira Ono Assistant Professor Christiane E. Wobus © Marta Jeannette Gonzalez‐Hernandez 2012 For my family and friends, the most fantastic teachers I have ever had. ii Acknowledgements First, and foremost, I would like to thank David Markovitz for his patience and his scientific and mentoring endeavor. My time in the laboratory has been an honor and a pleasure. Special thanks are also due to all the members of the Markovitz laboratory, past and present. It has been a privilege, and a lot of fun, to work near such excellent scientists and friends. You all have a special place in my heart. I would like to thank all the members of my thesis committee for all the valuable advice, help and jokes whenever needed. Our collaborators from the Bioinformatics Core, particularly James Cavalcoli, Fan Meng, Manhong Dai, Maureen Sartor and Gil Omenn gave generous support, technical expertise and scientific insight to a very important part of this project. Thank you. Thanks also go to Mariana Kaplan’s and Akira Ono’s laboratory for help with experimental designs and for being especially generous with time and reagents. iii Table of Contents Dedication ............................................................................................................................ ii Acknowledgements ............................................................................................................. iii List of Figures ...................................................................................................................
    [Show full text]
  • HIV 101: Pathogenesis and Treatment
    HIV 101: Pathogenesis and Treatment Stephen Raffanti MD MPH Professor of Medicine Vanderbilt University School of Medicine . Dr. Raffanti has no financial disclosures to make. Objectives . After this presentation the attendee should be able to: . Describe current issues in the epidemiology of the HIV epidemic. Describe the life cycle of HIV; . Describe the way that HIV interacts with its host, producing disease. Describe the principles of treatment. Describe Acute HIV infection . Describe the initial evaluation of an HIV infected patient Testing, linkage to care, effective treatment and effective PrEP could stop the epidemic today. Percentages of Diagnoses of HIV Infection among Adults and Adolescents, by Region and Population of Area of Residence, 2015—United States Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. Data for the year 2015 are preliminary and based on 6 months reporting delay. Data exclude persons whose county of residence is unknown. Percentages of Diagnoses of HIV Infection among Adults and Adolescents, by Population of Area of Residence and Age at Diagnosis, 2015—United States Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. Data for the year 2015 are preliminary and based on 6 months reporting delay. Data exclude persons whose county of residence is unknown. Diagnoses of HIV Infection among Men Who Have Sex with Men, by Age Group, 2010–2014—United States and 6 Dependent Areas Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays and missing transmission category, but not for incomplete reporting.
    [Show full text]
  • Lentivirus Vector Fact Sheet
    LENTIVIRUS VECTOR FACT SHEET LENTIVIRUSES: Lentiviral vector constructs are derived from HIV and are therefore highly efficient vehicles for in vivo gene delivery. Use of these vector systems is particularly desirable because of their ability to integrate transgenes into dividing, as well as, non-dividing cells. However, there are risks associated with working with lentiviral vectors and these must be carefully evaluated. The two major risks are: 1) the potential generation of replication competent virus; and 2) the potential for oncogenesis through insertional mutagenesis. These risks are largely based upon the vector system used and the transgene insert encoded by the vector. Therefore, it is imperative that prior to utilizing a lentiviral vector system, a risk assessment must be completed and documented. Also, because construction and/or use of lentiviral vectors falls under the definition of rDNA research as outlined in the NIH Recombinant DNA Guidelines, possession must be reported in the workplace’s biological agent inventory and experiments must be submitted for review and approval by the site IBC prior to initiation. Typically, lentiviral vectors may be safely handled using either BSL-2 or BSL-2 enhanced controls depending upon the risk assessment. LENTIVIRAL VECTORS: Lentiviruses can infect not only dividing, but also non-dividing host cells, because their pre-integration complex (virus “shell”) can get through the intact membrane of the nucleus of the target cell. Lentiviral vectors can be used to provide highly effective gene therapy as they can provide long-term expression of the vectored transgene in target cells. First-generation lentiviral vectors were manufactured using a single vector packaging system that contained all HIV genes, except the envelope (env) gene, in one plasmid.
    [Show full text]
  • VMC 321: Systematic Veterinary Virology Retroviridae Retro: from Latin Retro,"Backwards”
    VMC 321: Systematic Veterinary Virology Retroviridae Retro: from Latin retro,"backwards” - refers to the activity of reverse RETROVIRIDAE transcriptase and the transfer of genetic information from RNA to DNA. Retroviruses Viral RNA Viral DNA Viral mRNA, genome (integrated into host genome) Reverse (retro) transfer of genetic information Usually, well adapted to their hosts Endogenous retroviruses • RNA viruses • single stranded, positive sense, enveloped, icosahedral. • Distinguished from all other RNA viruses by presence of an unusual enzyme, reverse transcriptase. Retroviruses • Retro = reversal • RNA is serving as a template for DNA synthesis. • One genera of veterinary interest • Alpharetrovirus • • Family - Retroviridae • Subfamily - Orthoretrovirinae [Ortho: from Greek orthos"straight" • Genus -. Alpharetrovirus • Genus - Betaretrovirus Family- • Genus - Gammaretrovirus • Genus - Deltaretrovirus Retroviridae • Genus - Lentivirus [ Lenti: from Latin lentus, "slow“ ]. • Genus - Epsilonretrovirus • Subfamily - Spumaretrovirinae • Genus - Spumavirus Retroviridae • Subfamily • Orthoretrovirinae • Genus • Alpharetrovirus Alpharetrovirus • Species • Avian leukosis virus(ALV) • Rous sarcoma virus (RSV) • Avian myeloblastosis virus (AMV) • Fujinami sarcoma virus (FuSV) • ALVs have been divided into 10 envelope subgroups - A , B, C, D, E, F, G, H, I & J based on • host range Avian • receptor interference patterns • neutralization by antibodies leukosis- • subgroup A to E viruses have been divided into two groups sarcoma • Noncytopathic (A, C, and E) • Cytopathic (B and D) virus (ALV) • Cytopathic ALVs can cause a transient cytotoxicity in 30- 40% of the infected cells 1. The viral envelope formed from host cell membrane; contains 72 spiked knobs. 2. These consist of a transmembrane protein TM (gp 41), which is linked to surface protein SU (gp 120) that binds to a cell receptor during infection. 3. The virion has cone-shaped, icosahedral core, Structure containing the major capsid protein 4.
    [Show full text]
  • Protocol and Reagents for Pseudotyping Lentiviral Particles with SARS-Cov-2 Spike Protein for Neutralization Assays
    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.20.051219; this version posted April 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 of 15 Protocol and reagents for pseudotyping lentiviral particles with SARS-CoV-2 Spike protein for neutralization assays Katharine H.D. Crawford 1,2,3, Rachel Eguia 1, Adam S. Dingens 1, Andrea N. Loes 1, Keara D. Malone 1, Caitlin R. Wolf 4, Helen Y. Chu 4, M. Alejandra Tortorici 5,6, David Veesler 5, Michael Murphy 7, Deleah Pettie 7, Neil P. King 5,7, Alejandro B. Balazs 8, and Jesse D. Bloom 1,2,9,* 1 Division of Basic Sciences and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; [email protected] (K.D.C.), [email protected] (R.E.), [email protected] (A.S.D.), [email protected] (K.M.), [email protected] (A.N.L.) 2 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA 3 Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA 4 Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98195, USA; [email protected] (C.R.W.), [email protected] (H.Y.C.) 5 Department of Biochemistry, University of Washington, Seattle, WA 98109, USA; [email protected] (M.A.T.), [email protected] (D.V.), [email protected] (M.M.), [email protected] (D.P.), [email protected] (N.P.K.) 6 Institute
    [Show full text]
  • Lentivirus-Mediated Gene Transfer to the Respiratory Epithelium: a Promising Approach to Gene Therapy of Cystic fibrosis
    Gene Therapy (2004) 11, S67–S75 & 2004 Nature Publishing Group All rights reserved 0969-7128/04 $30.00 www.nature.com/gt REVIEW Lentivirus-mediated gene transfer to the respiratory epithelium: a promising approach to gene therapy of cystic fibrosis E Copreni, M Penzo, S Carrabino and M Conese Institute for Experimental Treatment of Cystic Fibrosis, HS Raffaele, Milano, Italy Gene therapy of cystic fibrosis (CF) lung disease needs logous envelopes are the strategies currently used to highly efficient delivery and long-lasting complementation overcome the paucity of specific viral receptors on the apical of the CFTR (cystic fibrosis transmembrane conductance surface of airway epithelial cells and to reach the basolateral regulator) gene into the respiratory epithelium. The develop- surface receptors. Preclinical studies on CF mice, demon- ment of lentiviral vectors has been a recent advance in the strating complementation of the CF defect, offer hope that field of gene transfer and therapy. These integrating vectors lentivirus gene therapy can be translated into an effective appear to be promising vehicles for gene delivery into treatment of CF lung disease. Besides a direct targeting of respiratory epithelial cells by virtue of their ability to infect the stem/progenitor niche(s) in the CF airways, an alternative nondividing cells and mediate long-term persistence of approach may envision homing of hematopoietic stem cells transgene expression. Studies in human airway tissues and engineered to express the CFTR gene by lentiviral vectors. animal models have highlighted the possibility of achieving In the context of lentivirus-mediated CFTR gene transfer gene expression by lentiviral vectors, which outlasted the to the CF airways, biosafety aspects should be of primary normal lifespan of the respiratory epithelium, indicating concern.
    [Show full text]
  • Lentiviral Integration Site Targeting: Host Determinants and Consequences
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations Spring 2010 Lentiviral Integration Site Targeting: Host Determinants and Consequences Keshet Ronen University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Virology Commons Recommended Citation Ronen, Keshet, "Lentiviral Integration Site Targeting: Host Determinants and Consequences" (2010). Publicly Accessible Penn Dissertations. 174. https://repository.upenn.edu/edissertations/174 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/174 For more information, please contact [email protected]. Lentiviral Integration Site Targeting: Host Determinants and Consequences Abstract A necessary step in the retroviral lifecycle is integration, the covalent insertion of the viral cDNA into the genome of the infected cell. This means that retroviruses, for example HIV, establish life-long infection. It also means that retroviruses are used as gene-delivery vectors to treat genetic diseases. Integration events are distributed non-randomly in the genome of the infected cell, with characteristic genus-specific preferences. In this dissertation, we focus on the lentiviral class of retroviruses, and explore two aspects of their integration: the means by which integration is targeted to its favored sites, and the consequences of integration at these sites for the host cell. The host protein LEDGF/p75 has been shown to interact with lentiviral integrases and contribute to their preference for integration in genes. We sought to establish the extent to which integration site selection is determined by LEDGF/p75 tethering. We first asked whether LEDGF/p75 was an essential integration tether, by analyzing integration site distribution in cells stringently depleted for LEDGF/p75.
    [Show full text]
  • Ovine Pulmonary Adenocarcinoma Is Caused by a Virus That Can Be Transmitted Adenocarcinoma Between Sheep in Respiratory Secretions Or Milk
    Ovine Pulmonary Importance Ovine pulmonary adenocarcinoma is caused by a virus that can be transmitted Adenocarcinoma between sheep in respiratory secretions or milk. Infections result in fatal pulmonary neoplasia in some animals, while others remain subclinically infected for life. The Ovine Pulmonary Adenomatosis, economic impact can be significant: 30-80% of the flock may be lost on first exposure Ovine Pulmonary Carcinoma, to the virus, with continuing annual losses that can be as high as 20% in some flocks, although 1-5% is more usual. Excluding this disease from a flock is difficult, in part Jaagsiekte, because no diagnostic test can reliably detect animals in the preclinical stage. No Sheep Pulmonary Adenomatosis effective treatment or vaccine is available, and eradication is challenging. Ovine pulmonary adenocarcinoma occurs in most sheep-raising areas of the world, with the exception of a few countries such as New Zealand and Australia. Iceland is the only Last Updated: March 2019 country known to have successfully eradicated this disease. Etiology Ovine pulmonary adenocarcinoma results from infection by jaagsiekte sheep retrovirus (JSRV), a member of the genus Betaretrovirus in the Retroviridae. JSRV is also known as the pulmonary adenomatosis virus. It has never been cultured from infected animals, which must be identified with viral nucleic acids or antigens. However, infectious virus has been constructed from molecular clones of JSRV, and these viruses can cause tumors in experimentally infected sheep. Species Affected Ovine pulmonary adenocarcinoma mainly affects sheep. Cases have also been reported in captive mouflon (Ovis musimon) and rarely in goats. Zoonotic potential Some authors have speculated that JSRV or a related human virus might be involved in the pathogenesis of certain types of lung cancer in people.
    [Show full text]
  • 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.
    [Show full text]