DOCSLIB.ORG

Identification of Cellular Host HIV Restriction Factors and Host- Pathogen Interactions

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Identification of Cellular Host HIV Restriction Factors and Host- Pathogen Interactions Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2015 Identification of cellular HIV restriction factors and host-HIV interactions Gers-Huber, Gustavo Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-122436 Dissertation Published Version Originally published at: Gers-Huber, Gustavo. Identification of cellular HIV restriction factors and host-HIV interactions. 2015, University of Zurich, Faculty of Science. Identification of Cellular HIV Restriction Factors And Host-HIV Interactions Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Gustavo Gers-Huber von Winterthur, ZH Promotionskomitee Prof. Dr. Michael Hottiger (Vorsitz) Prof. Dr. Roberto F. Speck (Leitung der Dissertation) Prof. Dr. Urs Greber Zürich, 2015 1 To Gustavo Huber Luna and J. Fernando Huber Lora 2 Table of contents Zusammenfassung ...................................................................................................................... 5 Summary .................................................................................................................................... 6 1. Introduction ....................................................................................................................... 7 1.1 The human immunodeficiency virus (HIV) type-1 .............................................................. 8 1.1.1 HIV epidemiology ................................................................................................... 8 1.1.2 HIV Genome ............................................................................................................ 9 1.1.3 HIV structure ........................................................................................................... 9 1.1.4 HIV replication cycle ............................................................................................. 10 1.1.5 HIV sequence evolution ......................................................................................... 13 1.1.6 HIV infection ......................................................................................................... 14 1.2 IFN-α-induced cellular restriction factors and HIV-1 accessory proteins ...................... 18 1.3 Modelling HIV infection and therapies in humanized mice ........................................... 67 2. Rationale and Aims ......................................................................................................... 80 2.1 Specific Aims .................................................................................................................. 81 2.2 Rationale of this thesis .................................................................................................... 81 3. Results ............................................................................................................................. 83 3.1 Analysis of the IFN-α signature by Next-Generation Sequencing in MT4 and SupT1 cells allows the identification of candidate genes for restriction factors against HIV-1 .... ........................................................................................................................................ 84 3.2 Development of a humanized mouse model for HIV infection .................................... 117 3 3.2.1 Long-acting anti-retroviral drugs for treating HIV-1 in humanized mice ........... 117 3.2.2 High resolution mapping of HIV drug resistance evolution driven by APOBEC3G .............................................................................................................................. 130 3.2.3 Gene Therapy against HIV-1 using the humanized mice .................................... 147 4. Discussion ..................................................................................................................... 160 4.1 Identification of potential IFN-stimulated HIV-1 restriction factors ............................ 161 4.2 The development of humanized mice models to study mechanisms of HIV infection .... 166 4.2.1 Long-acting anti-retroviral drugs for treating HIV-1 in humanized mice................. 166 4.2.2 High resolution mapping of HIV drug resistance evolution driven by APOBEC3G ..... ............................................................................................................................................ 167 4.2.3 Gene therapy against HIV-1 using the humanized mice ........................................... 170 Acknowledgements ................................................................................................................ 171 Curriculum Vitae .................................................................................................................... 173 Personal data .......................................................................................................................... 173 References .............................................................................................................................. 177 4 Zusammenfassung Das Humane Immundefizienz-Virus Typ 1 (HIV-1) ist das Pathogen, welches verantwortlich ist für das erworbene Immundefizienzsyndrom (AIDS). Die Verbreitung von HIV-1 hat sich zu einer Pandemie entwickelt, mit weltweit mehr als 35 Millionen infizierten Menschen und jährlich neuen Infektionen. Trotz der verfügbaren, effizienten antiretroviralen Therapie (ART) steigt das Erscheinen von Medikamentenresistenz mit der Zeit und der Zugang zu ART ist beschränkt in Entwicklungsländern. Aus diesem Grund ist es notwendig, neue Strategien zu entwickeln für das Blockieren der Virusreplikation und nach einer permanenten Heilung zu suchen. Eines der Ziele dieser Doktorarbeit war die Identifizierung neuer zellulärer anti-HIV-1 Wirtsfaktoren, welche potenziell als neue therapeutische Ansätze benutzt werden können. Die meisten der bisher identifizierten Restriktionsfaktoren sind IFN--induzierbar und werden neutralisiert durch akzessorische HIV-1 Proteine. Wir suchten nach Restriktionsfaktoren in CD4+ T-Zellinien, in denen die HIV-1 Replikation stark inhibiert wurde durch IFN-. Wir identifizierten 44 mögliche Kandidaten in den beiden Zellinien, die möglicherweise zwischen der reversen Transkription und Integration eingreifen. Ein zweites Ziel dieser Doktorarbeit war es, ein verbessertes Wissen über den Beitrag der Hypermutationsaktivität des bekannten Restriktionsfaktors APOBEC3G (A3G) zur HIV-1 Evolution in vivo zu erlangen. A3G wurde hauptsächlich in vitro auf seine mutagene Kapazität untersucht. Zu diesem Zweck verwendeten wir die humanisierte Maus als Modell für die HIV-1 Infektion. In humanisierten Mäusen ist das Immunsystem defizient und wird rekonstituiert mit humanen hämatopoetischen Vorläuferzellen, die ein Immunsystem humaner Herkunft entwickeln, welches die HIV-1 Infektion in Mäusen erlaubt. Wir studierten Virusreplikation und Diversifizierung in Mäusen, die mit einer HIV-1 Mutante infiziert worden waren, welche unfähig ist, die Hypermutationsaktivität von A3G vollständig zu neutralisieren (Vif 45G). Wir beobachteten, dass die Infektion mit dieser Mutante nicht in einem erhöhten Erscheinen der Medikamentenresistenz resultierte, wie bisherig angenommen, sondern eher die virale Fitness von HIV-1 unter selektivem Druck erhöhte. 5 Summary Human immunodeficiency virus type -1 (HIV-1) is the pathogen responsible for the acquired immunodeficiency syndrome (AIDS). HIV-1 is pandemic, affecting more than 35 million people worldwide and there are newly infected people every year. Despite the efficient anti- retroviral therapies (ART) available, the emergence of drug resistance increases overtime and the access to ART is very limited in developing countries. Therefore it is necessary to develop new strategies to block viral replication and to seek for a permanent cure. Restriction factors are cellular proteins aiming at inhibiting pathogen invasion. One of the aims of this thesis was to identify new cellular host HIV-1 restriction factors, which potentially can be used as a new therapeutic approach. Key features or signatures of currently known restriction factors are i) IFN-α-inducible and ii) counteracted by HIV-1 accessory proteins. We screened for restriction factors in CD4+ T-cell lines in which HIV-1 replication was strongly inhibited by IFN-α. We identified 44 possible candidates that might act between viral reverse transcription and integration in two cell lines. A second aim of this thesis was to evaluate or explore the contribution of the hypermutation activity of the known restriction factor APOBEC3G (A3G) to HIV-1 evolution in vivo. A3G has been mainly characterized in vitro for its mutagenic capacity. To this end, we used the humanized mouse as a model for HIV-1 infection. In humanized mice, the immune system is deficient and reconstituted with human hematopoietic precursor cells, which develop an immune system of human origin, allowing HIV- infection in mice. We studied viral replication and diversification in mice infected with a HIV-1 mutant which is unable to completely counteract A3G’s hypermutation activity (Vif 45G). We observed that infection with this mutant did not result in an increased drug resistance appearance, as previously thought, but it rather increased the viral fitness of HIV-1 under selective pressure. 6 1. Introduction 7 The introduction of this thesis
Load more

Recommended publications
  • Mechanisms of HIV Persistence in HIV Reservoirs
    Mechanisms of HIV persistence in HIV reservoirs 1. Mayibongwe Louis Mzingwane* Department of Medical Virology, Faculty of Health Sciences, University of Pretoria, P. Bag X323, ARCADIA 0007, Pretoria, South Africa Department of Pathology, Faculty of Medicine, National University of Science and Technology, P. O Box AC 939, Ascot, Bulawayo, Zimbabwe Email: [email protected] 2. Caroline T. Tiemessen Centre for HIV and Sexually Transmitted Infections, National Institute of communicable Diseases, Private Bag X4, Sandringham, 2131, Johannesburg, South Africa Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Email: [email protected] *Corresponding author Keywords: HIV reservoirs, persistent viremia Running head: HIV compartments and persistence 1 Summary The establishment and maintenance of HIV reservoirs which lead to persistent viremia in patients on antiretroviral (ARV) drugs remains the greatest challenge of the highly active antiretroviral therapy (HAART) era. Cellular reservoirs include resting memory CD4+ T lymphocytes, these implicated as the major HIV reservoir, having a half-life of approximately 44 months while this is less than 6 hours for HIV in plasma. In some individuals persistent viremia consists of invariant HIV clones not detected in circulating resting CD4+ T lymphocytes suggesting other possible sources of residual viremia. Some anatomical reservoirs that may harbour such cells include the brain and the central nervous system (CNS), the gastrointestinal tract (GIT) and the gut-associated lymphoid tissue (GALT) and other lymphoid organs and the genital tract. The presence of immune cells and other HIV susceptible cells, occurring in differing compositions in anatomical reservoirs, coupled with variable and poor drug penetration which results in suboptimal drug concentrations in some sites, are all likely factors that fuel the continued low level replication and persistent viremia during treatment.
    [Show full text]
  • Directed Evolution of an HIV-1 LTR Specific Recombinase for Anti-Retroviral Therapy- a Proof of Concept Study
    Directed evolution of an HIV-1 LTR specific recombinase for anti-retroviral therapy- a proof of concept study. DISSERTATION zur Erlangung des akademischen Grades Doctor rerum naturalium (Dr. rer. nat.) vorgelegt der Fakultät Mathematik und Naturwissenschaften der Technischen Universität Dresden von INDRANI SARKAR geboren am 03.12.1974, Kolkata, INDIA. Gutachter: Dr. Frank Buchholz Prof. Dr. Francis Stewart Prof. Dr. Joachim Hauber Eingereicht am 14.06.2006 Tag der Verteidigung: i Acknowledgements First and foremost I would like to thank my supervisor, Frank Buchholz for giving me the opportunity to work in his group and for motivating and supporting me through all these years. I am extremely grateful to him for having unlimited patience especially during the long evolution phase of this project and for always giving me helpful advice. He has been very supportive and reassuring in every situation. I am also thankful to him for the great lab retreats he organized. I would like to thank my TAC committee member Francis Stewart for his helpful suggestions. I am grateful to Joachim Hauber and Ilona Hauber (Heinrich-Pette Institute, Hamburg) who collaborated with me on this project and helped me to develop this project and provided me with the HIV-1 LTR based vectors and cell lines. I would like to thank Bianca Habermann for modeling of mutations and also Mayte Pissabarro with whom I had first looked into the recombinase mutations. A special thanks to all my lab members who made the lab a nice place to work in and also MPI-CBG for the friendly and cooperative atmosphere.
    [Show full text]
  • HIV Cure Research: Advances and Prospects
    HIV cure research: advances and prospects. Caroline P Passaes, Asier Sáez-Cirión To cite this version: Caroline P Passaes, Asier Sáez-Cirión. HIV cure research: advances and prospects.. Virology, Elsevier, 2014, 454-455, pp.340-52. 10.1016/j.virol.2014.02.021. pasteur-01420527 HAL Id: pasteur-01420527 https://hal-pasteur.archives-ouvertes.fr/pasteur-01420527 Submitted on 24 Apr 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - NonCommercial - ShareAlike| 4.0 International License HIV cure research: advances and prospects Caroline P. Passaesa,b, Asier Saez-Ciriona a Unité de Régulation des Infections Rétrovirales, Institut Pasteur, 25–28 rue du Dr Roux, 75724 Paris Cedex 15, France. b CEA, Division of Immuno-Virology, iMETI/DSV, 18 Route du Panorama, 92265 Fontenay-aux-Roses, France. Email addresses: [email protected]/[email protected] [email protected] Corresponding author: Asier Saez-Cirion Unité de Régulation des Infections Rétrovirales - Institut Pasteur 25–28 rue du Dr Roux, 75724 Paris Cedex 15, France Tel: +33 145688944; Fax: +33 145688957 E-mail: [email protected] 1 Abstract Thirty years after the identification of HIV, a cure for HIV infection is still to be achieved.
    [Show full text]
  • CONFERENCE CAROUSEL Editor’S Letter
    MARCH-APRIL 2012 IAVIReportThe Publication on AIDS Vaccine Research WWW.IAVIREPORT.ORG | VOLUME 16, NUMBER 2 CROI AND KEYSTONE: CONFERENCE CAROUSEL EDITor’s lETTER When managing editor Kristen Jill Kresge informed her staff that she was leaving the editing of IAVI Report in my hands while she went off to have a baby, I imagine their response was, well, polite. Or maybe not: Kristen is, as subscribers to this magazine doubtless know, a tough act to follow, even temporarily. Fortunately for me, she had the grace—and good sense—to plan out the issue before she went on leave. Aware that major HIV conferences were looming, Kristen dispatched her reporters to cover them. You will notice that they did so with gusto. Our sweeping report from the 19th Conference on Retrovi- ruses and Opportunistic Infections (CROI) may not qualify as light summer reading, but it does have a little something for everybody (see page 4). It recounts how researchers are harnessing new technolo- gies to solve the structure of the recalcitrant HIV spike, and shares insights gleaned from the continu- ing analysis of samples collected during the RV144 trial, which demonstrated for the first time that a wvaccine can prevent HIV transmission. Another segment delves into similar analyses of trials evaluat- ing antiretroviral treatment as a mode of prevention. For those with an appetite for basic biology, the article includes absorbing descriptions of HIV’s interaction with an elusive subclass of T helper cells, and research parsing the evolution of HIV’s intracellular defenses. Our articles on the Keystone Symposia this season are much more focused.
    [Show full text]
  • Highlights from the 2014 International Symposium on HIV
    Lafeuillade et al. AIDS Research and Therapy 2014, 11:28 http://www.aidsrestherapy.com/content/11/1/28 RESEARCH Open Access Highlights from the 2014 International Symposium on HIV & Emerging Infectious Diseases (ISHEID): from cART management to the end of the HIV pandemic Alain Lafeuillade1*, Mark Wainberg2, Marie-Lise Gougeon3, Sabine Kinloch-de Loes4, Philippe Halfon5 and Hervé Tissot-Dupont6 Abstract The 2014 International Symposium on HIV and Emerging Infectious Diseases (ISHEID) provided a forum for investigators to hear the latest research developments in the clinical management of HIV and HCV infections as well as HIV cure research. Combined anti-retroviral therapy (c-ART) has had a profound impact on the disease prognosis and transformed this infection into a chronic disease. However, HIV is able to persist within the infected host and the pandemic is still growing. The main 2014 ISHEID theme was, hence “Together for a world without HIV and AIDS”. In this report we not only give details on this main topic but also summarize what has been discussed in the areas of HCV coinfection and present a short summary on currently emerging viral diseases. Keywords: HIV, HCV, Hepatitis E, Antiretroviral drugs, HIV vaccine, HIV cure, HIV reservoirs Introduction The conference started by “The Thirty Years of Dis- The 2014 International Symposium on HIV and Emerging coveries of HIV” and “The Ten Big Mistakes We Did”. Infectious Diseases (ISHEID) was held in Marseille, Stefano Vella reminded us of the hopes in the early days France, on May 21-23. This meeting attracted more than of the epidemic of a prophylactic vaccine within the next 900 delegates from all over the world (75% outside France) 3 years.
    [Show full text]
  • Abstracts from the International Symposium HIV & Emerging Infectious Diseases 2014 Marseille, France
    BMC Infectious Diseases 2014, Volume 14 Suppl 2 http://www.biomedcentral.com/bmcinfectdis/supplements/14/S2/ MEETING ABSTRACTS Open Access Abstracts from the International Symposium HIV & Emerging Infectious Diseases 2014 Marseille, France. 21-23 May 2014 Published: 23 May 2014 These abstracts are available online at http://www.biomedcentral.com/bmcinfectdis/supplements/14/S2/ Conclusion: UDS was more sensitive than the standard Sanger ORAL PRESENTATIONS sequencing. A combination of UDS and DeepChek® software for the interpretation of DR results saved a considerable amount of time and would help clinicians provide suitable treatments. A cut-off of 1% allowed MANAGING ANTIRETROVIRAL THERAPY, a better characterization of the viral population by identifying additional PART 1 resistance mutations and improving the DR interpretation. O1 Clinical impact of ultra deep versus Sanger sequencing detection of O2 minority mutations on HIV-1 drug resistance genotype interpretation First-line therapy with LPV/r vs NVP and 2 NRTIs in a developing after virological failure country: W144 of a randomized trial Sofiane Mohamed1,4*, Guillaume Penaranda1, Dimitri Gonzalez2, Claire Camus1, Nathan Clumeck*, Claude Mwamba, Kabamba Kabeya, Vincent Calvez, Hacène Khiri1, Ronan Boulmé2, Chalom Sayada2, Patrick Philibert3, Serge Matanda, Dolorès Vaira, Gilles Peytavin, Coca Necsoi, Marc Delforge, Daniel Olive4, Philippe Halfon1 David Kadiebwe, Chantal Milolo, Joe Ilunga, Liévin Kapend 1Alphabio Laboratory, Marseille, France; 2Advanced Biological Laboratories Saint Pierre University Hospital, Brussels, Belgium (ABL), Luxembourg, Luxembourg; 3European Hospital, Marseille, France; BMC Infectious Diseases 2014, 14(Suppl 2):O2 4Paoli Calmettes Institute, Tumor Immunology Laboratory and INSERM Center of Cancer Research, Marseille, France Aim: In resource-limited countries, NNRTI-based regimen may result in BMC Infectious Diseases 2014, 14(Suppl 2):O1 emergence of more HIV drug resistance because of a low genetic barrier.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,871,516 B2 Hauber Et Al
    USOO887.1516 B2 (12) United States Patent (10) Patent No.: US 8,871,516 B2 Hauber et al. (45) Date of Patent: Oct. 28, 2014 (54) USE OF TAILORED RECOMBINASES FOR (56) References Cited THE TREATMENT OF RETROVRAL INFECTIONS U.S. PATENT DOCUMENTS 6,262,341 B1 7/2001 Baszczynski et al. (75) Inventors: Joachim Hauber, Hamburg (DE); 6,890,726 B1 5/2005 Sauer et al. Frank Buchholz, Dresden (DE); Ilona 7,112,715 B2 9, 2006 Chambon et al. Hauber, Hamburg (DE); Francis A 2006, OO14264 A1 1/2006 Sauer et al. Stewart, Dresden (DE); Indrani 2009/0217400 A1* 8/2009 Carmi et al. .................... 800, 14 Sarkar, Kolkata (IN) FOREIGN PATENT DOCUMENTS (73) Assignees: Technische Universität Dresden, WO O2/44409 A2 6, 2002 Dresden (DE); WO 2005/081632 A2 * 9, 2005 Max-Planck-Gesellschaft Zur WO 2008/083931 A1 T 2008 Forderung der Wissenschaften E.V. OTHER PUBLICATIONS München (DE); Heinrich-Pette-Institut fir Experimentelle Virologie und Abremski et al., “Studies on the Properties of P1 Site-Specific Immunologie an der Universität Recombination: Evidence for Topologically Unlinked Products fol Hamburg, Hamburg (DE) lowing Recombination.” Cell 32: 1301-1311, Apr. 1983. Abremski et al., “Bacteriophage P1 Site-specific Recombination— (*) Notice: Subject to any disclaimer, the term of this Purification and Properties of the Cre Recombinase Protein.” J. Biol. patent is extended or adjusted under 35 Chem. 259(3): 1509-1514, Feb. 10, 1984. U.S.C. 154(b) by 651 days. Adachi et al., “Production of Acquired Immunodeficiency Syn drome-Associated Retrovirus in Human and Nonhuman Cells (21) Appl.
    [Show full text]
  • New Treatments and Targets
    NEW TREATMENTS AND TARGETS P174 Universal Tre (uTre) recombinase specifically targets the majority of HIV-1 isolates Karpinski, J*; Chemnitz, J; Hauber, I; Abi-Ghanem, J; Paszkowski-Rogacz, M; Surendranath, V; Chakrabort, D; Hackmann, K; Schröck, E; Pisabarro, M; Hauber, J; Buchholz, F (Dresden, Germany) P175 Targeted destruction of HIV positive cells Sharma, J*; Dodgen, C; Skepu, A; Meyer, M (Cape Town, South Africa) *Indicates presenting author. Universal Tre (uTre) recombinase specifically targets the majority of HIV-1 isolates Janet Karpinski1, Jan Chemnitz2, Ilona Hauber2, Helga Hofmann-Sieber2, Carola Schäfer2, Niklas Beschorner2, Josephine Abi-Ghanem3, Maciej Paszkowski- Rogacz1, Vineeth Surendranath4, Debojyoti Chakraborty1, Karl Hackmann5, Evelin Schröck5, María Teresa Pisabarro3, Joachim Hauber2, Frank Buchholz1,4 1Department of Medical Systems Biology, Medical Faculty Carl Gustav Carus, TU Dresden, Germany, 2Heinrich Pette Institute - Leibniz Institute for Experimental Virology, Hamburg, Germany, 3Department of Structural Bioinformatics, TU Dresden, Germany, 4Max-Planck-Institute for Molecular Cell Biology and Genetics, Dresden, Germany, 5Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, TU Dresden, Germany ABSTRACT Background: Current drugs against HIV can suppress the progression to AIDS but Methods: We employed the search tool SeLOX [3] in Results: Highly specific enzymatic activity on loxLTRu is demonstrated for cannot clear the patient from the virus. Because of potential side effects of these drugs order to find a well-conserved HIV-1 proviral sequence uTre in both Escherichia coli and human cells. Naturally occurring viral variants and the possible development of drug resistance, finding a cure for HIV infection that could serve as target site for a universal Tre from with single mutations within the loxLTRu sequence are also shown to be remains a high priority of HIV/AIDS research.
    [Show full text]
  • NIH Public Access Author Manuscript Clin Pharmacol Ther
    NIH Public Access Author Manuscript Clin Pharmacol Ther. Author manuscript; available in PMC 2014 March 05. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Clin Pharmacol Ther. 2013 January ; 93(1): 46–56. doi:10.1038/clpt.2012.202. Prospects for Treatment of Latent HIV KM Barton1, BD Burch2, N Soriano-Sarabia2, and DM Margolis1,2,3 1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA 2Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA 3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Abstract Recent advances in antiretroviral therapy (ART) have drastically improved the quality of life for people with HIV infection. However, owing to the persistence of latent HIV in the presence of therapy, patients must remain on therapy indefinitely. Currently, the solution to the HIV pandemic rests on the prevention of new infections and many decades of ART for the steadily expanding number of people infected worldwide. ART is costly, requires ongoing medical care, and can have side effects, thereby preventing its universal availability. Therefore, to escape the ironic burdens of therapy, efforts have begun to develop treatments for latent HIV infection. Current approaches propose either complete eradication of infection or induction of a state of stringent control over viral replication without ART. This review will discuss these strategies in detail and their potential for clinical development. More than 30 million people are currently infected with HIV, and more than two million became newly infected in 2010.1 Significant progress has been made in the treatment of HIV infection, and current therapies allow infected individuals to attain near-normal life spans.
    [Show full text]
  • Tat-Independent Lentivirus Genomes for Vaccination and Host/Pathogen Interaction Studies Deepanwita Bose
    Tat-independent lentivirus genomes for vaccination and host/pathogen interaction studies Deepanwita Bose To cite this version: Deepanwita Bose. Tat-independent lentivirus genomes for vaccination and host/pathogen interac- tion studies. Human health and pathology. Université Grenoble Alpes, 2017. English. NNT : 2017GREAV009. tel-01938074 HAL Id: tel-01938074 https://tel.archives-ouvertes.fr/tel-01938074 Submitted on 28 Nov 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE Pour obtenir le grade de DOCTEUR DE LA COMMUNAUTÉ UNIVERSITÉ GRENOBLE ALPES Spécialité : Virologie/Microbiologie/Immunologie Arrêté ministériel : 7 août 2006 Présentée par Deepanwita BOSE Thèse dirigée par Dr. Yahia Chebloune préparée au sein du Laboratoire Pathogénèse et Vaccination Lentivirales (PAVAL Lab) dans l'École Doctorale Chimie & Sciences du Vivant (ED218) Tat-independent lentivirus genomes for vaccination and host/pathogen interaction studies. Thèse soutenue publiquement le 26 Janvier 2017, devant le jury composé de : Dr. Giuseppe Bertoni Maitre de conférences, IVI, Bern, Suisse Rapporteur Pr. Francois Villinger Professeur, Director of New Iberia Research Center, USA, Rapporteur Pr. Philippe Sabatier Professeur à l’Université Grenoble Alpes, Président Dr.Yahia Chebloune Research Director, à l’Université Grenoble Alpes, Examinateur Dr.
    [Show full text]
  • A M S J HIV/AIDS: Let’S See How Far We’Ve Come
    Review Article A M S J HIV/AIDS: let’s see how far we’ve come Lauren Fowler Lauren is a third year medical student at Griffith University. She has an undergraduate degree Third Year Medicine (Undergraduate) in science from the University of Sydney, and completed immunology honours in HIV retroviral Griffith University genetics, studying microRNA changes during HIV infection. She has a passion for the intricacies BSc (Hons) of the immune system and the pursuit of a cure for HIV. Now more than ever, HIV positive people are living longer and healthier lives because of access to antiretroviral therapy. Healthcare organisations are working to ensure that HIV positive people all over the world have access to the medical care they need to stay healthy. In the last few years, research into vaccine development, genetics-based approaches and novel therapies have achieved some progress and drug therapy regimens have become more effective. Public health strategies have aimed to reduce transmission, and early access to treatment has dramatically improved quality of life. With resources and funding aimed in the right directions, it will be possible to continue making significant progress towards better prevention, improved treatment options and perhaps even a cure for HIV and the elimination of the global AIDS epidemic. This article reviews some of the successes and difficulties in the scientific, research and treatment arm of infection progression to AIDS, and divides the infection into stages combating the HIV epidemic. There is still much work to be done, reflecting the decline in immune function. [11] The stages of infection but for now, let’s see how far we’ve come.
    [Show full text]
  • Directed Evolution of a Recombinase That Excises the Provirus of Most
    ARTICLES Directed evolution of a recombinase that excises the provirus of most HIV-1 primary isolates with high specificity Janet Karpinski1,2,11, Ilona Hauber2,11, Jan Chemnitz2,11, Carola Schäfer2,3, Maciej Paszkowski-Rogacz1, Deboyoti Chakraborty1, Niklas Beschorner2, Helga Hofmann-Sieber2,3, Ulrike C Lange2–4, Adam Grundhoff2,3, Karl Hackmann5, Evelin Schrock5, Josephine Abi-Ghanem6, M Teresa Pisabarro6, Vineeth Surendranath7, Axel Schambach8, Christoph Lindner9, Jan van Lunzen2,3,10, Joachim Hauber2,3 & Frank Buchholz1,7 Current combination antiretroviral therapies (cART) efficiently suppress HIV-1 reproduction in humans, but the virus persists as integrated proviral reservoirs in small numbers of cells. To generate an antiviral agent capable of eradicating the provirus from infected cells, we employed 145 cycles of substrate-linked directed evolution to evolve a recombinase (Brec1) that site- specifically recognizes a 34-bp sequence present in the long terminal repeats (LTRs) of the majority of the clinically relevant HIV-1 strains and subtypes. Brec1 efficiently, precisely and safely removes the integrated provirus from infected cells and is efficacious on clinical HIV-1 isolates in vitro and in vivo, including in mice humanized with patient-derived cells. Our data suggest that Brec1 has potential for clinical application as a curative HIV-1 therapy. Although substantial advances have been made in the treatment of HIV We now report the development and application of the broad-range infection using cART, present therapies do not cure HIV-infected indi- recombinase 1 (Brec1) that is active against the majority of HIV-1 viduals1–3. A small population of latent, transcriptionally silent but still primary isolates.
    [Show full text]