rologie i - European Congress of Virology

5 th European Congress of VirologyWednesday 11 th September 2013,16h15 – 18h15WORKSHOP 8: “ANTIVIRAL THERAPY ANDRESISTANCE TO ACUTE VIRAL INFECTION”Chairpersons: Johan NEYTS (Leuven, BELGIUM)& Manuel ROSA-CALATRAVA (Lyon, FRANCE)Amphitheatermembrane spanning protein of the viral replication complex corroboratethat K22 interferes with membrane bound viral RNA synthesis. This novelapproach is also applicable to diverse animal and human CoVs, includingthe recently identified HCoV EMC, and efficient inhibition can be achievedat the entry port of human CoV infection, the human airway epithelium.Collectively, we identified the recruitment of cellular membranes for viralreplication as a promising target for antiviral intervention. As replication atcellular membranes is a key step in the life cycle of many positive strandedRNA viruses, this approach may serve as a paradigm for the developmentof antiviral drugs to combat many other important virus infections.KEYNOTE:Antiviral Therapy and Resistance during acute viral infectionCharles BOUCHERDepartment of Virology Erasmus Medical Centre, Erasmus UniversityRotterdam, THE NETHERLANDSThe viral inoculum required for a successful viral infection is generallyquite small. Very early in HIV infection a nearly homogeneous viral wildtype population is found. The absence of viral variation enhances the efficacyof therapy because selection of preexisting resistance viruses is verylow. For example treatment with a low genetic drug (oseltamivir) veryrarely results in selection of single mutant resistant influenza. Under certainconditions selection of drug resistant may occur, for Influenza, HCV orHIV viruses the initial selected resistant viruses have a reduced replicativepotential. Continuous selection can lead to multiple additional compensatorymutations resulting in resistant viruses with a compensated replicationpotential. As a result of large scale spread use of antiviral drugs such compensatedresistant viruses can be transmitted and start sub epidemics (asreported for HIV) or can be the start of a global epidemic of resistance asobserved for Influenza in 2008. We study the rate of transmission of HIVand Influenza and subsequent evolution and its clinical significance.ORAL COMMUNICATIONSREF O07Potent inhibition of diverse Coronaviruses by targeting membranebound viral RNA synthesisEveline KINDLER 1 , A. LUNDIN 2 , R. DIJKMAN 1 , T. BERGSTROM 2 ,N. KANN 3 , B. ADMIAK 2 , C. HANNOUN 1 , H.R. JÓNSDÓTTIR 1 ,D. MUTH 4 , M.A. MÜLLER 4 , C. DROSTEN 4 , V. THIEL 1 ,E. TRYBALA 21 Institute of Immunobiology,Kantonal Hospital, St.Gallen, SWITZER-LAND; 2 Department of Clinical Virology, University of Gothenborg,Gothenborg, SWEDEN; 3 Chalmers University of Technology, Gothenborg,SWEDEN; 4 Institute of Virology, University of Bonn, Bonn,GERMANYThe concept of targeting key functions of the viral replication cycle ledto the development of potent antiviral drugs against HIV, influenza, andrecently HCV. Although targeting of multiple viral functions or enzymaticactivities resulted in highly active antiviral therapies, virus resistanceremains a concern. Therefore, there is an need to identify novel and druggabletargets to improve antiviral therapy. By screening more than 16 ′ 000compounds for anti human coronavirus 229E activity, we identified apotent inhibitor designated K22 that specifically targets membrane boundcoronavirus (CoV) RNA synthesis. Formation of virus induced doublemembrane vesicles, a hallmark of CoV replication, was impaired uponK22 treatment, which manifested a near complete inhibition of viral RNAsynthesis. Resistance mutants containing amino acid substitutions in aREF O08Discovery of low molecular weight compounds inhibiting Chikungunyavirus RNA replicationTero AHOLA 1 , Pasi KAUKINEN 1 , Finny VARGHESE 1 , MaximBESPALOV 2 , Krister WENNERBERG 2 , Andres MERITS 3 , BeateKUMMERER 41 University of Helsinki, Helsinki, FINLAND; 2 Institute for MolecularMedicine Finland, Helsinki, FINLAND; 3 University of Tartu, Tartu, ESTO-NIA; 4 University of Bonn Medical Centre, Bonn, GERMANYChikungunya virus (CHIKV) (genus Alphavirus) causes in humans highfever, body rash, headache and severe joint pain that can persist for monthsor years. The re emergence of CHIKV caused a large epidemic on LaRéunion Island in 2005 2006 and the virus subsequently spread to Indiaand South East Asia causing millions of infections. Endemic CHIKV infectionshave also been reported in Italy and France. CHIKV is transmitted inhumans by the bite of infected yellow fever mosquito (Aedes aegypti) orAsian tiger mosquito (Aedes albopictus). Currently, there is no vaccine orspecific drugs available to treat CHIKV infection. In this study, a CHIKVreplicon cell line expressing the virus replicase proteins and replicatingviral RNA was used in an antiviral screening assay with approximately3000 compounds. We identified several low molecular weight compoundsthat target the intracellular step of CHIKV replication. The most activecompounds were validated in CHIKV infection assay in human Huh7cells in combination with toxicity counter screening. We identified six hitcompounds, which showed dose dependent inhibition of CHIKV and therelated Semliki Forest virus with half maximal inhibitory concentration(IC50) below 3 micro Molar. As some of the compounds strongly modifiedthe localization of viral membrane bound replication complexes inCHIKV infected cells, they may affect general membrane properties. Therefore,some of the inhibitors could have broad spectrum antiviral activity.Isolation and analysis of drug resistant mutant viruses is currently beingpursued.REF O09Humanized antibodies able to protect mice from tick borne encephalitisNina TIKUNOVA 1 , Andrey MATVEEV 1 ,IvanBAIKOV 1 , LeonidMATVEEV 1 , Oleg STRONIN 21 Institute of Chemical Biology and Fundamental Medicine, Novosibirsk,RUSSIA; 2 Federal State Unitary Company Microgen Scientific IndustrialCompany for Immunobiological Medicines, Tomsk, RUSSIAAntibodies are used for therapy for a long time due to their exceptionalproperties – high specificities, availability of effector functions, andinvolvement of natural mechanisms in pharmacokinetics of administratedantibodies. There is currently no specific therapeutic strategy approved foruse in human tick borne encephalitis (TBE) in Europe. Specific immunoglobulinproduced from donor blood is used for TBE treatment in Russiabut this preparation has some disadvantages. Recombinant therapeuticantibodies offer an obvious alternative to donor’s immunoglobulin.Virologie, Vol 17, supplément 2, septembre 2013S41