Armando Arias Esteban

Armando Arias Esteban

Researcher

Kemitorvet

Building: 202, 2236

2800 Kgs. Lyngby

Denmark

RNA viruses replicate with large mutation frequencies which enable them with adaptability to a changing environment such as, for example, infecting a different host cell or organism, evading the immune system, or acquiring resistance to an antiviral compound. Thus, the resulting virus populations are complex clouds of mutant genomes also known as virus quasispecies. Alterations in the genetic diversity of a virus quasispecies can drastically affect its infectivity and pathogenesis, hence novel antiviral strategies based on manipulating virus mutation frequencies have recently emerged. I am particularly interested in lethal mutagenesis which consists in leading a virus infection to extinction through an artificial increase of virus mutation frequency.

 

I initiated my research career in 1999 in the laboratory of Esteban Domingo (CBMSO Madrid), after completing BSc studies in the Universidad Autonoma de Madrid, to investigate basic aspects on virus quasispecies diversity and molecular memory. During subsequent postdoctoral studies I became interested in understanding virus replication at the structural and molecular level (collaborations with Nuria Verdaguer and Craig Cameron) focusing on the FMDV polymerase. These studies permitted us to gain insight in the molecular mechanisms underlying replication fidelity and lethal mutagenesis of viruses.

 

In 2010 I joined Ian Goodfellow’s lab (Imperial College London; University of Cambridge) where I worked on the development of animal models to study persistent norovirus replication. We demonstrated that norovirus persistence can be cured by the use of a novel mutagenic compound with unapparent toxicity for the host. We have recently demonstrated that a norovirus with altered polymerase fidelity showed delayed transmission in vivo suggesting that viral genetic diversity may have an impact in the epidemiological success of RNA viruses. In addition to these studies focused on the molecular biology of viruses with emphasis on their replication, I have recently participated in a fascinating study in Sierra Leone where we tracked Ebola virus evolution dynamics during the recent epidemics. We will seek for opportunities to resume our investigations in Africa to the identification of novel emerging threats to global health.

 

My recently established group aims at further investigating the influence of polymerase fidelity and genetic diversity on viral pathogenesis. We will also evaluate different strategies based on lethal mutagenesis in the control of disease caused by different viruses.

 

Opportunities: Although no vacancies are available at the moment, I am happy to receive enquiries from highly motivated individuals seeking funded positions as well as those willing to apply for studentships or fellowships.

 

CV

Education

1994 - 1999 BSc - Universidad Autónoma de Madrid
1999 - 2005 PhD - Universidad Autónoma de Madrid

Academic grades

PhD Molecular Biology

BSc Biochemistry

Professional experience

1999 - 2005 PhD student - CBM Severo Ochoa Madrid
2005 - 2010 Research associate - CBM Severo Ochoa Madrid
2010 - 2012 Research associate - Imperial College London
2012 - 2015 Research associate - University of Cambridge

Languages

English, Spanish

Expertise

I am a Virologist with vast experience in replication fidelity, genetic diversity, and evolution of RNA viruses. My main areas of research are:

  1.  Lethal mutagenesis in vivo. We have recently investigated the development of antiviral therapies based on lethal mutagenesis. A persistent norovirus infection in mice can be cleared by lethal mutagenesis using a novel mutagenic compound, named favipiravir (Arias et al 2014 eLife). These studies have led to clinical trial prospects, in collaboration with UK clinical researchers, for the treatment of chronic diarrhoea caused by norovirus in immunocompromised patients, a life threatening condition.
  2. Identification of polymerase fidelity determinants in the virus polymerase and their role in pathogenesis. We have recently demonstrated that a norovirus fidelity mutant displays reduced transmission in vivo with possible epidemiologic implications discussed (Arias et al 2016 mSphere). We have isolated diverse FMDV polymerase fidelity variants and characterised them structurally and in cell culture (Arias et al 2008 JVI; Agudo et al 2010 PLoS Pathog).
  3. Evolution dynamics and transmission chain of Ebola virus during the recent epidemics in Sierra Leone. With this aim, we have established a research laboratory in Makeni for in situ sequencing of Ebola virus strains circulating in country.
  4. Establishment of mouse models to study persistent infections in vivo (Arias et al 2012JGV, McFadden et al 2013 NAR).
  5. Structural-functional characterisation of virus replication complexes. In collaboration with Prof Verdaguer we have resolved different FMDV polymerase replication complexes: initiation, RNA binding, incorporation of nucleotides, and fidelity (Ferrer-Orta et al 2006 EMBO; 2007 PNAS).

International experience

 

During my research career I have had the opportunity to work in Spain, UK, and USA with different outstanding researchers mentioned below (Esteban Domingo, Ian Goodfellow, Dave Rowlands, Craig Cameron), allowing me now to expand my international collaboration network:

Research positions

  1. University of Cambridge (UK). Postdoc with Prof Ian Goodfellow. October 2012-August 2015. Development of antiviral strategies to control norovirus in vivo.
  2. Imperial College London (UK). Postdoc with Prof Ian Goodfellow. 2010-2012. Establishment of a norovirus infection mouse model.
  3. CBM Severo Ochoa (Spain). Prof Esteban Domingo:
  • Postdoctoral position. 2005-2010. Fidelity determinants of RNA virus replication.
  • PhD studies. 1999-2005. Isolation and in vitro characterisation of FMDV polymerase.

 

Short research projects in host international institutions

  1. Ebola Treatment Centre Makeni (Sierra Leone). April-July 2015. Prof Ian Goodfellow. In situ sequencing of Ebola virus circulating in country.
  2. PennState University (USA). May-July 2006. Prof Craig Cameron. FMDV polymerase characterization and identification of fidelity determinants.
  3. University of Leeds (UK). February-May 2004. Prof David Rowlands. FMDV capsid in vitro assembly studies.

Other information

 

PUBLICATIONS

 

Peer-reviewed papers

  1. Arias A† (corresponding authors), Thorne L, Ghurburrun E, Bailey D, Goodfellow I† (2016). Norovirus polymerase fidelity contributes to viral transmission in vivo. mSphere, 1: e00279-16. This paper was selected by the Editor as a monthly highlight.
  2. Arias A, Watson SJ, Asogun D, Tobin EA, Lu J, Phan MVT, Jah U, Wadoum REG, Meredith L, Thorne L, Caddy S, Tarawalie A, Langat P, Dudas G, Faria NR, Dellicour S, Kamara A, Kargbo B, Kamara BO, Gevao S, Cooper D, Newport M, Horby P, Dunning J, Sahr F, Brooks T, Simpson AJH, Groppelli E, Liu G, Mulakken N, Rhodes K, Akpablie J, Yoti Z, Lamunu M, Vitto E, Otim P, Owilli C, Boateng I, Okoror L, Omomoh E, Oyakhilome J, Omiunu R, Yemisis I, Adomeh D, Ehikhiametalor S, Akhilomen P, Aire C, Kurth A, Cook N, Baumann J, Gabriel M, Wölfel R, Di Caro A, Carroll MW, Günther S, Redd J, Naidoo D, Pybus OG, Rambaut A, Kellam P, Goodfellow I, Cotten M. (2016). Rapid outbreak sequencing of Ebola virus in Sierra Leone identifies transmission chains linked to sporadic cases. Virus Evol, 2, vew016
  3. Thorne L.†, A. Arias (joint first authors), I. Goodfellow (2016). Advances toward a norovirus antiviral: from classical inhibitors to lethal mutagenesis. J Infect Dis, 213, S27-S31
  4. Dunning J, Sahr F, Rojek A, Gannon F, Carson G, Idriss B, Massaquoi T, Gandi R, Joseph S, Osman HK, Brooks TJG, Simpson AJH, Goodfellow I, Thorne L, Arias A, Merson L, Castle L, Howell-Jones R, Pardinaz-Solis R, Hope-Gill B, Ferri M, Grove J, Kowalski M, Stepniewska K, Lang T, Whitehead J, Olliaro P, Samai M, Horby PW. 2016. Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial. PLoS Med 13:e1001997.
  5. Agudo R, de la Higuera I, Arias A, Grande-Pérez A, Domingo E. 2016. Involvement of a joker mutation in a polymerase-independent lethal mutagenesis escape mechanism. Virology 494:257–66.                                 
  6. Smits SL, Pas SD, Reusken CB, Haagmans BL, Pertile P, Cancedda C, Dierberg K, Wurie I, Kamara A, Kargbo D, Caddy SL, Arias A, Thorne L, Lu J, Jah U, Goodfellow I, Koopmans MP. (2015). Genotypic anomaly in Ebola virus strains circulating in Magazine Wharf area, Freetown, Sierra Leone, 2015. Euro Surveill 20:30035.
  7. Arias A. (corresponding authors), L. Thorne, I. Goodfellow† (2014). Favipiravir elicits antiviral mutagenesis during virus replication in vivo. eLife 3, e03679.
  8. Hwang, S., Alhatlani, B., Arias, A., Caddy, S. L., Christodoulou, C., et al. (2014). Murine Norovirus: Propagation, Quantification, and Genetic Manipulation. Current Protocols in Microbiology 33:15K.2.1–15K.2.61.
  9. Arias A. (corresponding authors), E. Emmott, S. Vashist & I. Goodfellow† (2013). Progress towards the prevention and treatment of norovirus infections. Future Microb 8, 1475-1487.
  10. Arias A., A. I. de Ávila, M. Sanz-Ramos, R. Agudo, C. Escarmís & E. Domingo (2013). Molecular dissection of a viral quasispecies under mutagenic treatment: positive correlation between fitness loss and mutational load. J Gen Virol 94, 817 – 830
  11. McFadden N., A. Arias, I. Dry, D. Bailey, J. Witteveldt, D. J. Evans, I. Goodfellow & P. Simmonds (2013). Influence of genome-scale RNA structure disruption on the replication of murine norovirus-similar replication kinetics in cell culture but attenuation of viral fitness in vivo. Nucleic Acids Res 41:6316-31
  12. Arias A. (corresponding authors), D. Bailey, Y. Chaudhry & I. Goodfellow† (2012). Development of a reverse genetics system for murine norovirus 3; long-term persistence occurs in the caecum and colon. J Gen Virol 93, 1432-41.
  13. Arias A. (corresponding authors), L. Ureña, L. Thorne, M. A. Yunus, I. Goodfellow† (2012). Reverse genetics mediated recovery of infectious murine norovirus. J Vis Exp 64: e4145, DOI: 10.3791/4145.
  14. Ojosnegros S., J. García-Arriaza, C. Escarmís, S. C. Manrubia, C. Perales, A. Arias, M. G. Mateu & E. Domingo (2011). Viral genome segmentation can result from a trade-off between genetic content and particle stability. PLoS Genet 7, e1001344.
  15. Arias, A., C. Perales, C. Escarmís & E. Domingo (2010). Deletion mutants of VPg reveal new cytopathology determinants in a picornavirus. PLoS ONE 5, e10735.
  16. Agudo, R., C. Ferrer-Orta, A. Arias, I. de la Higuera, C. Perales, R. Pérez-Luque, N. Verdaguer & E. Domingo (2010). A multi-step process of viral adaptation to a mutagenic nucleoside analogue by modulation of transition types leads to extinction-escape. PLoS Pathog 6, e1001072.
  17. Ferrer-Orta, C., M. Sierra, I. de la Higuera, R. Agudo, A. Arias, R. Perez-Luque, C. Escarmis, E. Domingo & N. Verdaguer (2010). Structure of foot-and-mouth disease virus mutant polymerases with reduced sensitivity to ribavirin. J Virol. 84, 6188-99.
  18. Goodwin, S., T. J. Tuthill, A. Arias, R. A. Killington & D. J. Rowlands (2009). Foot-and-mouth disease virus assembly: processing of recombinant capsid precursor by exogenous protease induces self-assembly of pentamers in vitro in a myristoylation-dependent manner. J Virol 83, 11275-82.
  19. Agudo, R., A. Arias & E. Domingo (2009). 5-Fluorouracil in lethal mutagenesis of viruses. Future Medical Chemistry 1, 529-39.
  20. Arias, A., J. J. Arnold, M. Sierra, E. Smidansky, E. Domingo & C. Cameron (2008). Determinants of RNA-dependent RNA polymerase (in)fidelity revealed by kinetic analysis of the polymerase encoded by a foot-and-mouth disease virus mutant with reduced sensitivity to ribavirin. J Virol 82, 12346-55
  21. Agudo, R., A. Arias, N. Pariente, C. Perales, C. Escarmís, A. Jorge, A. Marina & E. Domingo (2008). Molecular characterization of a dual inhibitory and mutagenic activity of 5-fluorouridine-triphosphate on viral RNA synthesis. Implications for lethal mutagenesis. J. Mol. Biol. 382, 652-66.
  22. Escarmís, C., E. Lázaro, A. Arias & E. Domingo (2008). Repeated bottleneck transfers can lead to non-cytocidal forms of a cytopathic virus. Implications for viral extinction. J. Mol. Biol. 376, 367-79.
  23. Ferrer-Orta, C., A. Arias, R. Pérez-Luque, C. Escarmís, E. Domingo & N. Verdaguer (2007). Sequential structures provide insights into the fidelity of RNA replication. Proc Natl Acad Sci USA. 104, 9463-8.
  24. Sierra, M., A. Airaksinen, C. González-López, R. Agudo, A. Arias, & E. Domingo (2007). Foot-and-mouth disease virus mutant with decreased sensitivity to ribavirin: implications for error catastrophe. J Virol. 81, 2012-24.
  25. Ferrer-Orta†, C., A. Arias (joint first authors), R. Agudo, R. Pérez-Luque, C. Escarmís, E. Domingo & N. Verdaguer (2006). The structure of a protein primer-polymerase complex in the initiation of genome replication. EMBO J. 25, 880-8.
  26. Ferrer-Orta, C., A. Arias, C. Escarmís & N. Verdaguer (2006). A comparison of viral RNA-dependent RNA polymerases. Curr Opin Struct Biol. 16, 27-34.
  27. Arribas, M., A. de Vicente, A. Arias & E. Lázaro (2005). Effect of metallic cations on the efficiency of DNA amplification. Implications for nucleic acid replication during early stages of life. International J Astrobiology. 4, 115-23.
  28. Arias, A., R. Agudo, C. Ferrer-Orta, R. Pérez-Luque, A. Airaksinen, E. Brocchi, E. Domingo, N. Verdaguer & C. Escarmís (2005). Mutant viral polymerase in the transition of virus to error catastrophe identifies a critical site for RNA binding. J Mol Biol. 353, 1021-32.
  29. Ferrer-Orta, C., A. Arias, R. Pérez-Luque, C. Escarmís, E. Domingo & N. Verdaguer (2004). Structure of foot-and-mouth disease virus RNA-dependent RNA polymerase and its complex with a template-primer RNA. J Biol Chem. 279, 47212-21.
  30. Arias, A., C. M. Ruíz-Jarabo, C. Escarmís & E. Domingo (2004). Fitness increase of memory genomes in a viral quasispecies. J Mol Biol. 339, 405-12.
  31. González-López, C., A. Arias, N. Pariente, G. Gómez-Mariano & E. Domingo (2004). Preextinction viral RNA can interfere with infectivity. J Virol. 78, 3319-24.
  32. Ruíz-Jarabo, C. M., A. Arias, C. Molina-París, C. Briones, E. Baranowski, C. Escarmís & E. Domingo (2002). Duration and fitness dependence of quasispecies memory. J Mol Biol. 315, 285-96.
  33. Domingo, E., C. M. Ruíz-Jarabo, S. Sierra, A. Arias, N. Pariente, E. Baranowski & C. Escarmís (2002). Emergence and selection of RNA virus variants: memory and extinction. Virus Res. 82, 39-44.
  34. Arias, A., E. Lázaro, C. Escarmís & E. Domingo (2001). Molecular intermediates of fitness gain of an RNA virus: characterization of a mutant spectrum by biological and molecular cloning. J Gen Virol. 82, 1049-60.
  35. Ruíz-Jarabo, C. M., A. Arias, E. Baranowski, C. Escarmís & E. Domingo (2000). Memory in viral quasispecies. J Virol. 74, 3543-7.

 

Non-peer reviewed publcations

Book chapters

  1. Domingo, E., C. Perales, R. Agudo, A. Arias, C. Escarmís, C. Ferrer-Orta & N. Verdaguer (2010). Mutation, quasispecies and lethal mutagenesis. In: The Picornaviruses (E. Ehrenfeld, E. Domingo & R.P. Roos, eds.), 197-211. ASM Press, Washington, D.C.
  2. Domingo, E., V. Martín, C. Perales, A. Grande-Perez, J. García-Arriaza & A. Arias (2006). Viruses as quasispecies: biological implications. In “Quasispecies: concepts and implications for virology” (Domingo, E., ed.). Curr Topics Microbiol Immunol. 299, 51-82.
  3. Domingo, E., C. M. Ruíz-Jarabo, A. Arias, J. García-Arriaza & C. Escarmís (2004). Quasispecies dynamics and evolution of foot-and-mouth disease virus. In: Foot-and-mouth disease: current perspectives (Sobrino, F. & Domingo, E., eds.), pp. 261-304, Horizon Bioscience, Wymondham, England.
  4. Domingo, E., C. M. Ruíz-Jarabo, A. Arias, C. Molina-París, C. Briones, E. Baranowski & C. Escarmís (2003). Detection and biological implications of genetic memory in viral quasispecies. In Cardiomyopathies and Heart Failure: Biomolecular, Infectious and Immune Mechanisms (Matsumori, A., ed.), pp. 259-276, Kluwer Academic Publishers, London, United Kingdom.

 

Public release of data

  1. Goodfellow, I., A. Arias, S. Caddy, B. Kargbo, B. O. Kamara, U. Jah, D. Cooper, et al. (2015) Recent evolution patterns of Ebola virus inferred from patient samples collected from February-May 2015 with direct deep sequencing in Sierra Leone. http://virological.org
  2. Goodfellow, I., A. Arias, S. Caddy, L. Thorne, B. Kargbo, B. O. Kamara, U. Jah, et al. (2015) Recent evolution patterns of Ebola virus from December 2014-June 2015 obtained by direct sequencing in Sierra Leone. http://virological.org

 

Patents

  1. Method for the detection of minority genomes in virus quasispecies using DNA microchips. C. Briones, C. Martín, C. Escarmís, E. Baranowski, V. Parro. J. Gómez, E. Domingo, A. Arias. Application number: AU2004203139B2.
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    Society for General Microbiology, United Kingdom

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