HIV-1 Drug Resistance to Integrase Strand Transfer Inhibitors in HIV-1 Non-B Subtypes

Total Page:16

File Type:pdf, Size:1020Kb

HIV-1 Drug Resistance to Integrase Strand Transfer Inhibitors in HIV-1 Non-B Subtypes Western University Scholarship@Western Electronic Thesis and Dissertation Repository 4-20-2021 12:00 PM HIV-1 Drug Resistance to Integrase Strand Transfer Inhibitors in HIV-1 non-B Subtypes Emmanuel Ndashimye, The University of Western Ontario Supervisor: Arts, Eric J., The University of Western Ontario A thesis submitted in partial fulfillment of the equirr ements for the Doctor of Philosophy degree in Microbiology and Immunology © Emmanuel Ndashimye 2021 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Infectious Disease Commons, Medical Immunology Commons, Medical Microbiology Commons, Medical Molecular Biology Commons, Medical Pharmacology Commons, Virology Commons, and the Virus Diseases Commons Recommended Citation Ndashimye, Emmanuel, "HIV-1 Drug Resistance to Integrase Strand Transfer Inhibitors in HIV-1 non-B Subtypes" (2021). Electronic Thesis and Dissertation Repository. 7765. https://ir.lib.uwo.ca/etd/7765 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract Human immunodeficiency syndrome (HIV-1) has infected over 75 million people and over 35 million have succumbed to virus related illnesses. Despite access to a variety of antiretroviral therapy (ART) options, ART programs have been disproportionally spread in the world with low- and middle-income countries (LMICs) facing challenges to access the most potent ART options. With less potent ART remaining in use in LMICs, HIV-1 drug resistance (HIVDR) presents a growing challenge in LMICs. Since approval of the first-generation integrase strand transfer inhibitor (INSTIs), Raltegravir (RAL) in 2007, INSTIs remain the best choice as a backbone of ART. Access to second generation INSTIs, Dolutegravir (DTG) and bictegravir (BIC) in LMICs is based on need and not on a full evaluation of the effectiveness of these treatments in patients infected with non-B HIV-1 subtypes. To address this challenge of limited INSTIs associated HIVDR data in non-B HIV subtypes, we first screened for the presence of INSTIs associated drug resistance mutations (DRMs) in ART naïve and experienced patients in Uganda using Sanger and Illumina sequencing. In Uganda, 47% of patients failing on RAL carry resistance to RAL-and elvitegravir (EVG), and only 4% harbor resistant virus to DTG. A panel of recombinant viruses from patient-derived HIV-1 integrases carrying resistant mutations was created and tested for susceptibility to a panel of INSTIs: EVG, RAL, DTG, BIC, and CAB. The virus carrying N155H or Y143R/S was susceptible to DTG, BIC, and CAB but highly resistant to RAL and EVG (>50- fold change). Two patients, one with E138A/G140A/Q148R/G163R and one with E138K/G140A/S147G/Q148K, displayed the highest reported resistance to RAL, EVG (FC, >1000) and even DTG (FC, >100), BIC (FC, 60->100), and CAB (FC, 429->1000). All viruses had impaired replication fitness and <50% reduction in integration capacity. We further determined potential novel polymorphisms associated with INSTI resistance in HIV-1 subtype A and D using simple vector machine analysis. The identified I208L and I203M, did not show reduced susceptibility to RAL or DTG with 1.3-1.8-fold and 1-1.4-fold observed, respectively. Further investigation is required to determine how these novel mutations influence susceptibility to INSTIs in HIV-1 subtype A and D infected patients. ii Keywords HIV-1 non-subtype B, integrase strand transfer inhibitors, HIV-1 drug resistance, Low-and Middle-income countries, Uganda iii Summary for Lay Audience Human immunodeficiency syndrome virus type 1 (HIV-1) is the causative agent for Acquired immunodeficiency syndrome (AIDS) which is characterized by rapid depletion of CD4+ T cells which eventually results in emergence of opportunistic infections. HIV-1 like other retroviruses, hijack host DNA machinery to be able to replicate and cause havoc in the infected individual. Because of high replication rate and numerous errors during replication, there are diverse strains of HIV-1 circulating in world population which are commonly referred to as subtypes, circulating recombinant forms, and unique recombinant forms. The non-B HIV-1 subtypes are predominantly in low- and middle-income countries (LMICs) and account for up to ~ 90% of HIV-1 infections. The antiretroviral therapy (ART) has tremendously improved the lives of individuals infected with HIV-1 and discovery of an even more potent class of ART, the integrase strand transfer inhibitors (INSTIs) has further improved HIV-1 treatment outcomes. Despite these advances, research of HIV-1 drug resistance associated with INSTIs has historically been done in HIV-1 subtype B virus which is predominant in high-income countries. With improved access to INSTIs by HIV-1 patients in LMICs, there is urgent need to assess susceptibility of HIV-1 non-B strains to INSTIs and also discover novel potential pathways to resistance in these strains. From a cohort of HIV-1 infected patients in Uganda, we show that prolonged virological failure on INSTI, raltegravir, leads to accumulation of drug resistance mutations which confer resistance to all currently available INSTIs. Novel mutations in the HIV-1 integrase gene which show no impact on INSTIs susceptibility by themselves, may act as secondary mutations to other drug resistance mutations outside HIV-1 integrase gene which merits further investigation. iv Co-Authorship Statement I am the sole lead author of the first three manuscripts presented in this work. Though I am the second author in the fourth manuscript, I carried out much of the work presented including, sample collection, laboratory assays, participated in data analysis, and writing of the manuscript. Other co-authors of the manuscript each had a role in the study including designing of experiments, recruitment of patients, data analysis, writing and providing critical reviews of the manuscript. The authors list for the co-authored manuscript; Mariano Avino, Emmanuel Ndashimye, Daniel J. Lizotte, Abayomi S. Olabode, Richard, M. Gibson, Adam A. Meadows, Cissy M. Kityo, Eva Nabulime, Fred Kyeyune, Immaculate Nankya, Miguel E. Quin˜ones-Mateu, Eric J. Arts, Art F. Y. Poon. v Acknowledgments To my great supervisor and mentor, Dr Eric Arts, I very much appreciate the opportunity to learn from you and for making me the person I am today. Thank you for being more than a supervisor but also a great friend. I’m so grateful for your never-ending dedication, guidance, facilitation, and effort to make this work possible. My sincere gratitude also goes to my supervisory committee members, Dr Steve Barr, and Dr Michael Silverman for guiding me while undertaking the program. A special appreciation goes to the HIV-1 drug resistance teams in Uganda, Canada, and New Zealand which include Dr Miguel E. Quiñones-Mateu, Dr Art F.Y Poon, Dr Immaculate Nankya, Dr Fred Kyeyune, Dr Mariano Avino, and Dr Abayomi Samuel Olabode, for the fruitful collaborations which has made this work possible and as such helped in enhancing HIV-1 treatment research. The members of Dr Eric Arts, Jamie Mann, Yong Gao, Jessica Prodger, and Ryan Troyer laboratories at Western University, are all highly appreciated for sincere support, guidance, and encouragements. To my dear family, mother, Epiphanie Mpumugeni; father, Sylvester Nsengivunva; sister, Florence Uwamaliya; brothers, Ronald Hakiza, Olivier Ishimwe Rukundo, and Leon Ineza; thank you all for the support, encouragement, and love. You all sacrificed a lot for me and for that I will forever be grateful. Finally, to my loving wife, Enid Nayebare; children, Ethan Ndashimye, and Eli Ndashimye, thank you very much for bearing my frequent absence and standing with me as I went through this journey. May the good Lord continue to bless you and grant you good health. vi Table of Contents Abstract ............................................................................................................................. ii Summary for Lay Audience ............................................................................................. iv Co-Authorship Statement.................................................................................................. v Acknowledgments............................................................................................................ vi Table of Contents ............................................................................................................ vii List of Tables ................................................................................................................... xi List of Figures ................................................................................................................ xiii List of Appendices ......................................................................................................... xvi List of abbreviations ..................................................................................................... xvii Chapter 1 ........................................................................................................................... 1 1 Introduction .................................................................................................................. 1 1.1 HIV-1 ...................................................................................................................
Recommended publications
  • Impact of Natural HIV-1 Nef Alleles and Polymorphisms on SERINC3/5 Downregulation
    Impact of natural HIV-1 Nef alleles and polymorphisms on SERINC3/5 downregulation by Steven W. Jin B.Sc., Simon Fraser University, 2016 Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Science in the Master of Science Program Faculty of Health Sciences © Steven W. Jin 2019 SIMON FRASER UNIVERSITY Spring 2019 Copyright in this work rests with the author. Please ensure that any reproduction or re-use is done in accordance with the relevant national copyright legislation. Approval Name: Steven W. Jin Degree: Master of Science Title: Impact of natural HIV-1 Nef alleles and polymorphisms on SERINC3/5 downregulation Examining Committee: Chair: Kanna Hayashi Assistant Professor Mark Brockman Senior Supervisor Associate Professor Masahiro Niikura Supervisor Associate Professor Ralph Pantophlet Supervisor Associate Professor Lisa Craig Examiner Professor Department of Molecular Biology and Biochemistry Date Defended/Approved: April 25, 2019 ii Ethics Statement iii Abstract HIV-1 Nef is a multifunctional accessory protein required for efficient viral pathogenesis. It was recently identified that the serine incorporators (SERINC) 3 and 5 are host restriction factors that decrease the infectivity of HIV-1 when incorporated into newly formed virions. However, Nef counteracts these effects by downregulating SERINC from the cell surface. Currently, there lacks a comprehensive study investigating the impact of primary Nef alleles on SERINC downregulation, as most studies to date utilize lab- adapted or reference HIV strains. In this thesis, I characterized and compared SERINC downregulation from >400 Nef alleles isolated from patients with distinct clinical outcomes and subtypes. I found that primary Nef alleles displayed a dynamic range of SERINC downregulation abilities, thus allowing naturally-occurring polymorphisms that modulate this activity to be identified.
    [Show full text]
  • MS Ritgerð Aðalbjörg Aðalbjörnsdóttir
    The Vif protein of maedi-visna virus Protein interaction and new roles Aðalbjörg Aðalbjörnsdóttir Thesis for the degree of Master of Science University of Iceland Faculty of medicine School of Health Sciences Vif prótein mæði-visnuveiru Prótein tengsl og ný hlutverk Aðalbjörg Aðalbjörnsdóttir Ritgerð til meistaragráðu í Líf og læknavísindum Umsjónarkennari: Valgerður Andrésdóttir Meistaranámsnefnd: Stefán Ragnar Jónsson og Ólafur S. Andrésson Læknadeild Heilbrigðisvísindasvið Háskóla Íslands Júní 2016 The Vif protein of maedi-visna virus Protein interaction and new roles Aðalbjörg Aðalbjörnsdóttir Thesis for the degree of Master of Science Supervisor: Valgerður Andrésdóttir Masters committee: Stefán Ragnar Jónsson and Ólafur S. Andrésson Faculty of Medicine School of Health Sciences June 2016 Ritgerð þessi er til meistaragráðu í Líf og læknavísindum og er óheimilt að afrita ritgerðina á nokkurn hátt nema með leyfi rétthafa. © Aðalbjörg Aðalbjörnsdóttir 2016 Prentun: Háskólaprent Reykjavík, Ísland 2016 Ágrip Mæði-visnuveira (MVV) er lentiveira af ættkvísl retróveira. Hún veldur hæggengri lungnabólgu (mæði) og heilabólgu (visnu) í kindum. Aðalmarkfrumur veirunnar eru mónocytar/makrófagar. Veiran er náskyld HIV og hefur verið notuð sem módel fyrir HIV sýkingar. Stöðug vopnakapphlaup milli veira og fruma hafa leitt af sér fjölda sértækra aðferða í vörnum hýsilsfrumu gegn veirusýkingum. Fruman hefur þróað með sér innrænar varnir gegn ýmsum sýkingum. Þessar varnir geta verið mjög sérhæfðar og tjáning þeirra spilar stórt hlutverk í hvaða frumur er hægt að sýkja og hverjar ekki. Dæmi um slíkan frumubundinn þátt eru APOBEC3 próteinin. APOBEC3 próteinin eru fjölskylda cytósín deaminasa sem geta hindrað retróveirur og retróstökkla. Þetta gera þau með því að afaminera cýtósín í úrasil í einþátta DNA á meðan á víxlritun stendur og valda þar með G-A stökkbreytingum í forveirunni.
    [Show full text]
  • 718 HIV Disorders of the Brain; Pathology and Pathogenesis Luis
    [Frontiers in Bioscience 11, 718-732, January 1, 2006] HIV disorders of the brain; pathology and pathogenesis Luis Del Valle and Sergio Piña-Oviedo Center for Neurovirology and Cancer Biology, Laboratory of Neuropathology and Molecular Pathology, Temple University, 1900 North 12th Street, Suite 240, Philadelphia, Pennsylvania 19122 USA TABLE OF CONTENTS 1. Abstract 2. AIDS-Encephalopathy 2.1. Definition 2.2. HIV-1 Structure 2.3. Histopathology 2.4. Clinical Manifestations 2.5. Physiopathology 3. Progressive Multifocal Leukoencephalopathy 3.1. Definition 3.2. JC Virus Biological Considerations 3.3. JC Virus Structure 3.4. Histopathology 3.5. Clinical Manifestations 3.6. Physiopathology 4. Cryptococcosis 5.1. Definition 5.2. Cryptococcus neoformans Structure 5.3. Histopathology 5.4. Clinical Manifestations 5.5. Physiopathology 5. Toxoplasmosis 5.1. Definition 5.2. Toxoplasma godii Structure 5.3. Histopathology 5.4. Clinical Manifestations 5.5. Physiopathology 6. Primary CNS Lymphomas 6.1. Definition 6.2. Histopathology 6.3. Clinical Manifestations 6.4. Physiopathology 7. Acknowledgments 8. References 1. ABSTRACT Infection with HIV-1 has spread exponentially in still present in approximately 70 to 90% of patients and recent years to reach alarming proportions. It is estimated can be the result of HIV itself or of opportunistic than more than 33 million adults and 1.3 million children infections. Here we briefly review the pathology and are infected worldwide. Approximately 16,000 new cases pathophysiology of AIDS-Encephalopathy, of some of are diagnosed every day and almost 3 million people die the significant opportunistic infections affecting the every year from AIDS, making it the fourth leading brain in the context of AIDS, including Progressive cause of death in the world.
    [Show full text]
  • Review CCR5 Antagonists: Host-Targeted Antivirals for the Treatment of HIV Infection
    Antiviral Chemistry & Chemotherapy 16:339–354 Review CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection Mike Westby* and Elna van der Ryst Pfizer Global R&D, Kent, UK *Corresponding author: Tel: +44 1304 649876; Fax: +44 1304 651819; E-mail: [email protected] The human chemokine receptors, CCR5 and suggest that these compounds have a long plasma CXCR4, are potential host targets for exogenous, half-life and/or prolonged CCR5 occupancy, which small-molecule antagonists for the inhibition of may explain the delay in viral rebound observed HIV-1 infection. HIV-1 strains can be categorised by following compound withdrawal in short-term co-receptor tropism – their ability to utilise CCR5 monotherapy studies. A switch from CCR5 to (CCR5-tropic), CXCR4 (CXCR4-tropic) or both (dual- CXCR4 tropism occurs spontaneously in approxi- tropic) as a co-receptor for entry into susceptible mately 50% of HIV-infected patients and has been cells. CCR5 may be the more suitable co-receptor associated with, but is not required for, disease target for small-molecule antagonists because a progression. The possibility of a co-receptor natural deletion in the CCR5 gene preventing its tropism switch occurring under selection pressure expression on the cell surface is not associated by CCR5 antagonists is discussed. The completion with any obvious phenotype, but can confer of ongoing Phase IIb/III studies of maraviroc, resistance to infection by CCR5-tropic strains – the aplaviroc and vicriviroc will provide further insight most frequently sexually-transmitted strains. into co-receptor tropism, HIV pathogenesis and The current leading CCR5 antagonists in clinical the suitability of CCR5 antagonists as a potent development include maraviroc (UK-427,857, new class of antivirals for the treatment of HIV Pfizer), aplaviroc (873140, GlaxoSmithKline) and infection.
    [Show full text]
  • UC Merced UC Merced Undergraduate Research Journal
    UC Merced UC Merced Undergraduate Research Journal Title Antiviral Drugs Targeting Host Proteins an Efficient Strategy Permalink https://escholarship.org/uc/item/66f5b4m0 Journal UC Merced Undergraduate Research Journal, 9(2) Author Karmonphet, Arrada Publication Date 2017 DOI 10.5070/M492034789 Undergraduate eScholarship.org Powered by the California Digital Library University of California Antiviral Drugs Targeting Host Proteins an Efficient Strategy Arrada Karmonphet University of California, Merced Keywords: Proteins, Viruses, Drugs 1 Abstract Viruses have the ability to spread rapidly because the proteins and enzymes from the host cell help in the development of viruses. Although there are many vaccines that can prevent some viruses from infecting the body, the antiviral drugs today have not been effective in combating viruses from the start of spreading. This is due to the fact that the processes inside a virus are still being studied. However, host proteins proved to be valuable factors responsible for viral replication and spreading. It was found that certain functions such as capsid formation of the virus utilized a biochemical pathway that involved host proteins and some proteins of the host cell were evolutionarily conserved. When the important host proteins were altered, or removed the viruses weren’t able to replicate as effectively. It was concluded that targeting the host proteins had a significant effect in viral replication. This approach can stop viral replication from the start, create less viral resistance, and help find new antiviral drugs that work for many different types of viruses. This review will analyze five research articles about protein interactions in viruses and how monitoring the proteins and biochemical pathways can lead to the discovery of druggable targets during development.
    [Show full text]
  • Aplaviroc (APL, 873140)
    Hepatotoxicity observed in clinical trials of aplaviroc (APL, 873140) WG Nichols1, HM Steel1, TM Bonny1, SS Min1, L Curtis1, K Kabeya2, N Clumeck2 1 GlaxoSmithKline, Research Triangle Park, USA; 2 CHU-Saint-Pierre, Brussels, Belgium. Aplaviroc (APL, 873140, Ono 4128) O CH3 O HO • Specific CCR5 antagonist O N OH N NH • Potent HIV entry inhibitor O – mean 1.66 log10 decline at nadir in HIV-RNA after 10d monotherapy1 • Safety profile supported further study in humans 1 Lalezari J et al. AIDS 2005;19:1443–1448. Aplaviroc Phase 2b Program CCR100136 CCR102881 • 195 treatment-naïve • 147 treatment-naïve subjects randomized to subjects randomized to – APL 200mg BID / LPV/r – APL 600mg BID / Combivir – APL 400mg BID / LPV/r – APL 800mg BID / Combivir – APL 800mg QD / LPV/r – Combivir / efavirenz – LPV/r / Combivir – 2:2:1 randomisation – 2:2:2:1 randomization Sentinel case: Severe hepatitis • 39 year old HIV+ male – CD4 283 cells/mm3 – HBV/HCV negative – Normal AST/ALT/bilirubin • APL 800mg BID + COM • Day 59: developed severe hepatic cytolysis • Liver biopsy: – Chronic inflammatory infiltrate, mod intensity Liver biopsy (portal area) – Consistent with drug-induced hepatotoxicity CCR102881 Individual Patient LFT Plots ALP ALT AST BILT CK 70 60 50 40 30 APL RX 20 LFT Values (x ULN) 10 0 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100 Study Day Review of Liver Enzyme Elevations in APL Phase IIb trials • 336 subjects received treatment – 282 subjects on APL – median duration of therapy: 13 wks • Central Lab database query to identify – any Grade
    [Show full text]
  • Assessment of the Interaction Between the Human
    VARIATIONS IN THE V3 CROWN OF HIV-1 ENVELOPE IMPACT AFFINITY FOR CCR5 AND AFFECT ENTRY AND REPLICATIVE FITNESS By MICHAEL ANDREW LOBRITZ Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Dissertation advisor: Eric J. Arts, Ph.D. Department of Molecular Biology and Microbiology CASE WESTERN RESERVE UNIVERSITY August 2007 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ______________________________________________________ candidate for the Ph.D. degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. Table of Contents Chapter 1: Introduction........................................................................................................................16 1.A. HIV and AIDS..............................................................................................17 1.B. Retroviruses: Structure, Organization, and Replication...............................20 1.B.1. HIV-1 Genome...............................................................................20 1.B.2. HIV-1 Particle................................................................................23
    [Show full text]
  • Autophagy and Mammalian Viruses: Roles in Immune Response, Viral Replication, and Beyond
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2016 Autophagy and mammalian viruses: roles in immune response, viral replication, and beyond Paul, P ; Münz, C Abstract: Autophagy is an important cellular catabolic process conserved from yeast to man. Double- membrane vesicles deliver their cargo to the lysosome for degradation. Hence, autophagy is one of the key mechanisms mammalian cells deploy to rid themselves of intracellular pathogens including viruses. How- ever, autophagy serves many more functions during viral infection. First, it regulates the immune response through selective degradation of immune components, thus preventing possibly harmful overactivation and inflammation. Additionally, it delivers virus-derived antigens to antigen-loading compartments for presentation to T lymphocytes. Second, it might take an active part in the viral life cycle by, eg, facili- tating its release from cells. Lastly, in the constant arms race between host and virus, autophagy is often hijacked by viruses and manipulated to their own advantage. In this review, we will highlight key steps during viral infection in which autophagy plays a role. We have selected some exemplary viruses and will describe the molecular mechanisms behind their intricate relationship with the autophagic machinery, a result of host–pathogen coevolution. DOI: https://doi.org/10.1016/bs.aivir.2016.02.002 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-131236 Book Section Accepted Version The following work is licensed under a Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License.
    [Show full text]
  • Role of Reverse Transcriptase and APOBEC3G in Survival of Human
    & My gy co lo lo ro g i y V Soni et al., Virol Mycol 2013, 3:1 Virology & Mycology DOI: 10.4172/2161-0517.1000125 ISSN: 2161-0517 Review Article Open Access Role of Reverse Transcriptase and APOBEC3G in Survival of Human Immune Deficiency Virus -1 Genome Raj Kumar Soni*, Amol Kanampalliwar and Archana Tiwari School of Biotechnology, Rajiv Gandhi Proudyogiki Vishwavidyalaya (State Technological University), Madhya Pradesh, India Abstract Development of an effective vaccine against HIV-1 is a major challenge for scientists at present. Rapid mutation and replication of the virus in patients contribute to the evolution of the virus, which makes it unconquerable. Hence a deep understanding of critical elements related to HIV-1 is necessary. Errors introduced during DNA synthesis by reverse transcriptase are the primary source of genetic variation within retroviral populations. Numerous current studies have shown that apolipo protein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) proteins mediated sub- lethal mutagenesis of HIV-1 proviral DNA contributes in viral fitness by accelerating human immunodeficiency virus-1 evolution. This results in the loss of the immunity and development of resistance against anti-viral drugs. This review focuses on the latest biological, biochemical, and structural studies in an attempt to discuss current ideas related to mutations initiated by reverse transcriptase and APOBEC3G. It also describes their effect on immunological diversity and retroviral restriction, and their overall effect on the viral genome respectively. A new procedure for eradication of HIV-1 has also been proposed based on the previous studies and proven facts. Keywords: HIV-1; Reverse transcriptase; Recombination; defined.
    [Show full text]
  • To Reduce HIV-1 Infectivity Facilitates Its Encapsidation Into the Virions GANP Interacts with APOBEC3G
    GANP Interacts with APOBEC3G and Facilitates Its Encapsidation into the Virions To Reduce HIV-1 Infectivity This information is current as Kazuhiko Maeda, Sarah Ameen Almofty, Shailendra Kumar of September 23, 2021. Singh, Mohammed Mansour Abbas Eid, Mayuko Shimoda, Terumasa Ikeda, Atsushi Koito, Phuong Pham, Myron F. Goodman and Nobuo Sakaguchi J Immunol 2013; 191:6030-6039; Prepublished online 6 November 2013; Downloaded from doi: 10.4049/jimmunol.1302057 http://www.jimmunol.org/content/191/12/6030 Supplementary http://www.jimmunol.org/content/suppl/2013/11/06/jimmunol.130205 http://www.jimmunol.org/ Material 7.DC1 References This article cites 52 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/191/12/6030.full#ref-list-1 Why The JI? Submit online. by guest on September 23, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology GANP Interacts with APOBEC3G and Facilitates Its Encapsidation into the Virions To Reduce HIV-1 Infectivity Kazuhiko Maeda,*,1 Sarah Ameen Almofty,*,1 Shailendra Kumar Singh,* Mohammed Mansour Abbas Eid,* Mayuko Shimoda,* Terumasa Ikeda,†,2 Atsushi Koito,† Phuong Pham,‡ Myron F.
    [Show full text]
  • A Novel Small Molecule CCR5 Inhibitor Active Against R5-Tropic HIV-1S
    www.nature.com/scientificreports OPEN Activity and structural analysis of GRL-117C: a novel small molecule CCR5 inhibitor active against R5- Received: 24 September 2018 Accepted: 1 March 2019 tropic HIV-1s Published: xx xx xxxx Hirotomo Nakata1,2, Kenji Maeda 3, Debananda Das 1, Simon B. Chang1, Kouki Matsuda3, Kalapala Venkateswara Rao4, Shigeyoshi Harada5, Kazuhisa Yoshimura5, Arun K. Ghosh4 & Hiroaki Mitsuya1,2,3 CCR5 is a member of the G-protein coupled receptor family that serves as an essential co-receptor for cellular entry of R5-tropic HIV-1, and is a validated target for therapeutics against HIV-1 infections. In the present study, we designed and synthesized a series of novel small CCR5 inhibitors and evaluated their antiviral activity. GRL-117C inhibited the replication of wild-type R5-HIV-1 with a sub-nanomolar IC50 value. These derivatives retained activity against vicriviroc-resistant HIV-1s, but did not show activity against maraviroc (MVC)-resistant HIV-1. Structural modeling indicated that the binding of compounds to CCR5 occurs in the hydrophobic cavity of CCR5 under the second extracellular loop, and amino acids critical for their binding were almost similar with those of MVC, which explains viral cross- resistance with MVC. On the other hand, one derivative, GRL-10018C, less potent against HIV-1, but more potent in inhibiting CC-chemokine binding, occupied the upper region of the binding cavity with its bis-THF moiety, presumably causing greater steric hindrance with CC-chemokines. Recent studies have shown additional unique features of certain CCR5 inhibitors such as immunomodulating properties and HIV-1 latency reversal properties, and thus, continuous eforts in developing new CCR5 inhibitors with unique binding profles is necessary.
    [Show full text]
  • The Battle Between Retroviruses and APOBEC3 Genes: Its Past and Present
    viruses Review The Battle between Retroviruses and APOBEC3 Genes: Its Past and Present Keiya Uriu 1,2,†, Yusuke Kosugi 3,4,†, Jumpei Ito 1 and Kei Sato 1,2,* 1 Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan; [email protected] (K.U.); [email protected] (J.I.) 2 Graduate School of Medicine, The University of Tokyo, Tokyo 1130033, Japan 3 Laboratory of Systems Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 6068507, Japan; [email protected] 4 Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 6068501, Japan * Correspondence: [email protected]; Tel.: +81-3-6409-2212 † These authors contributed equally to this work. Abstract: The APOBEC3 family of proteins in mammals consists of cellular cytosine deaminases and well-known restriction factors against retroviruses, including lentiviruses. APOBEC3 genes are highly amplified and diversified in mammals, suggesting that their evolution and diversification have been driven by conflicts with ancient viruses. At present, lentiviruses, including HIV, the causative agent of AIDS, are known to encode a viral protein called Vif to overcome the antiviral effects of the APOBEC3 proteins of their hosts. Recent studies have revealed that the acquisition of an anti-APOBEC3 ability by lentiviruses is a key step in achieving successful cross-species transmission. Here, we summarize the current knowledge of the interplay between mammalian APOBEC3 proteins and viral infections and introduce a scenario of the coevolution of mammalian APOBEC3 genes and viruses. Keywords: APOBEC3; lentivirus; Vif; arms race; gene diversification; coevolution Citation: Uriu, K.; Kosugi, Y.; Ito, J.; Sato, K.
    [Show full text]