Santseharay Ramirez Almeida

Primary fields of research

My main area of research is the study of viruses. I have been interested in viruses for as long as I can remember, so it was an obvious choice for me to join a virology program for my undergraduate studies. It all started with the hepatitis C virus (HCV) a viral disease that causes 500,000 deaths every year.

During my Master and PhD studies, I had the privilege to be a member of the viral hepatitis unit at IDIBAPS-Hospital Clinic in Barcelona, Spain, a well-integrated team of clinicians and researchers creating a great environment for translational science. There I conducted studies about genetic evolution of HCV and viral and host determinants of infection recurrence in liver transplantation patients. Afterwards I looked for basic science and the opportunity to study viruses in culture. HCV still fascinated me, so I decided to continue with a postdoc in the HCV field, and relocate to the Copenhagen Hepatitis C Program (CO-HEP) in Denmark, a world leader in basic research on HCV. At CO-HEP I focused on basic aspects of the molecular biology of HCV, including the development of novel experimental systems. A challenge stood ahead: developing robust culture systems for the major genotypes of HCV, a virus that does not grow in vitro. After some time of hard and tenacious work we made a breakthrough developing full-length infectious cell culture systems of the major HCV genotypes, which are highly appreciated in the field. I am now focusing in the work with polymerase inhibitors, which led to a recent proof-of-concept finding: HCV can evolve to develop resistance to sofosbuvir (the blockbuster of HCV therapy). This drug class targets conserved elements critical for replication of RNA viruses, thus exhibiting broad-spectrum antiviral activity, a trend in antiviral research. One of the most relevant questions about these antivirals is if they will be able to neutralize the vast genetic evolution potential of viruses to evade antiviral strategies, or if in contrast, their broader spectrum comes at the cost of lower barrier to resistance? Currently, I am establishing a group at CO-HEP aiming at studying universal antivirals across RNA viruses, with the prospect of defining better antivirals that can address the global challenge of viral emerging diseases, and mimic the successful drug development for HCV, our model virus.

Current research

Development of cell culture systems for the study of HCV in vitro

Study of the molecular mechanisms of antiviral resistance against drugs used in the treatment of HCV

Study of the barrier to resistance of different classes of polymerase inhibitors with universal activity across RNA viruses

Teaching

 Lab Courses

Virology Courses (Øvelseskursus Virologi) for medical school students at PANUM, University of Copenhagen. (2016).

 Lectures at the Course In Immunology And General Microbiology (Modul: 3908-E16), KU

 Lectures / Teaching at CO-HEP

 Weekly meeting with the members of the CO-HEP research group (2009-present)

 Lectures / Teaching at the Department of Infectious Diseases, Hvidovre Hospital:

Meeting with medical personnel (2009-present)

Lectures at the Department Research Days

 Current teaching and supervision of students, scientists, and technicians:

Amanda Gammelby Qvesel. Bachelor Project in Molecular Biomedicine

Carlota Fernandez Antunez (B.Sc). Master Program in Biology (Microbiology)

Lotte Mikkelsen. Laboratory technician.

Possible conflicts of interest

None

CV

EDUCATION

1. Bachelor of Sciences-Biotechnology, July 26, 2004. Autonomous University of Barcelona
2. Master Thesis, July 17, 2007. Microbiology Department, Hospital Clinic, University of Barcelona; Supervisor: Dr.  Xavier Forns
3. PhD, February 2, 2010. Liver Unit, Hospital Clinic and Faculty of Medicine, University of Barcelona; Supervisor: Dr.  Xavier Forns

CURRENT AND MOST RECENT POSITIONS HELD

1. 2005-2009: Master and PhD Student, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona
2. 2009-2014:  Research assistant and postdoc, Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital
3. 2014-2016:  Postdoc, CO-HEP, Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology (ISIM), University of Copenhagen.
4. 2017-current: Associate Professor, CO-HEP, Department of Infectious Diseases, Hvidovre Hospital and ISIM, University of Copenhagen.

ACADEMIC AWARDS, HONOURS AND GRANTS

1. Pre-doctoral stipend, Institut D’Investigacions Biomèdiques August Pi i Sunyer, IDIBAPS (2006-2009); salary for my Ph.D.
2. Mobility Fellowship (2007); European Network for Vigilance against Viral Resistance, VirGIL (3.200 EURO)
3. Hvidovre Hospital Research Fond 2010 (50.000 DKK)
4. Individual post-doctoral stipend (2011-2013), Danish Council for Independent Research, Medical Sciences (1.835.180 DKK)
5. Region H Research Fond (2012-2016); Co-written with Jens Bukh (1.000.000 DKK)
6. Lundbeck Foundation (2012-2016); Co-written with Jens Bukh (2.000.000 DKK)
7. Danish Council for Independent Research, Medical Sciences (2012-2015); Co-written with Jens Bukh (4.067.243 DKK)
8. Danish Council for Independent Research, Medical Sciences, Sapere Aude: DFF-Advanced (2014-2019); Co-written with Jens Bukh (11.916.000 DKK)
9. A.P.Møller Fond for Medical Research (2018); Main applicant (40.000 DKK).

PARTICIPATION IN INTERNATIONAL SYMPOSIUMS

42^nd Annual Meeting of the European Association for the Study of the Liver. 2007, Barcelona, Spain.

International symposium on Hepatitis C virus and related viruses:

14^th: 2007, Glasgow, UK.

15^th: 2008, San Antonio, USA.

23^th: 2016.  Kyoto, Japan .

24^th: 2017. Cape Cod, USA .

Invited Speaker at Kanazawa University, 2016. Japan

SUPERVISION OF STUDENTS

MD Jannie Pedersen (Research Assistant and PhD student: 2010-2015). BSc, MSc, Long Van Pham (PhD student: 2014-present). MD Christina Sølund (medical and PhD student: 2012-2017). BSc, Carlota Fernandez (Master student: 2017-present). Amanda Gammelby Qvesel (Bachelor project student: 2018-present).

MANAGEMENT EXPERIENCE

BSc, MSc Nadia Hashem (Research Assistant). BSc, Robert Hayne (Full-Bright Fellow). Laboratory Technician, Lotte Mikkelsen (2014-present).

Introductory remarks on publicationslist

LIST OF PUBLICATIONS

25 Peer-reviewed publications, 6 first-author publications. 

2 Issued Patents, and 3 Patent Applications.

Metrics: Citations: 733. H-index: 14 (retrieved from Google Scholar March, 2018)

Researcher ID: R-9257-2016

ORCID: https://orcid.org/0000-0003-3699-1814

Scopus Author ID: 26023617700

Peer-reviewed publications (articles). Author role underlined and in bold face

1. Massaguer A, Ramirez S, Carrion JA, Gonzalez P, Sanchez-Tapias JM, Forns X. Evolution of the NS3   and NS5B regions of the hepatitis C virus during disease recurrence after liver transplantation. American Journal of Transplantation 2007; 7: 2172-79. 
2. Ramirez S, Perez-Del-Pulgar S, Forns X. Virology and pathogenesis of hepatitis C virus recurrence. Liver Transplantation 2008;14 Suppl 2:S27-35. Review. 
3. Carrion JA, Martinez-Bauer E, Crespo G, Ramirez S, Perez-Del-Pulgar S, Garcia-Valdecasas JC, Navasa M, Forns X. Antiviral therapy increases the risk of bacterial infections in HCV-infected cirrhotic patients awaiting liver transplantation: A retrospective study. Journal of Hepatology 2009; 50: 719-28.
4. Ramirez S, Perez-Del-Pulgar S, Carrion JA, Costa J, Gonzalez P, Massaguer A, Fondevila C, Garcia-Valdecasas JC, Navasa M, Forns X. Hepatitis C virus compartmentalization and infection recurrence after liver transplantation. American Journal of Transplantation 2009; 9: 1591-1601.
5. Ramirez S, Perez-Del-Pulgar S, Carrion JA, Coto-Llerena M, Mensa L, Dragun J, Garcia-Valdecasas JC, Navasa M, Forns X. Hepatitis C virus superinfection of liver grafts: a detailed analysis of early exclusion of non-dominant virus strains. Journal of General Virology 2010; 91: 1183-88.  
6. Li YP, Ramirez S, Gottwein JM, Bukh J. Non-genotype-specific role of the hepatitis C virus 5' untranslated region in virus production and in inhibition by interferon. Virology 2011; 421:222-34
7. Dragun J, Perez-Del-Pulgar S, Crespo G, Ramirez S, Coto-Llerena M, Mensa L, Garcia-Valdecasas JC, Navasa M, Forns X. Characterization of the cross-neutralizing antibody response against hepatitis C virus in the liver transplantation setting. American Journal of Transplantation 2011;11:767-74.
8. Li YP, Ramirez S, Gottwein JM, Scheel TK, Mikkelsen L, Purcell RH, Bukh J. Robust full-length hepatitis C virus genotype 2a and 2b infectious cultures using mutations identified by a systematic approach applicable to patient strains. Proceedings of the National Academy of Sciences USA 2012; 109: E1101-10. 
9. Li YP, Ramirez S, Jensen SB, Purcell RH, Gottwein JM, Bukh J. Highly efficient full-length hepatitis C virus genotype 1 (strain TN) infectious culture system. Proceedings of the National Academy of Sciences USA 2012; 109: 19757-62.  
10.  Pedersen J, Carlsen TH, Prentoe J, Ramirez S, Jensen TB, Forns X, Alter H, Foung SK, Law M,    Gottwein J, Weis N, Bukh J. Neutralization resistance of hepatitis C virus can be overcome by recombinant human monoclonal antibodies. Hepatology 2013; 58: 1587-97.
11. Carlsen TH, Scheel TK, Ramirez S, Foung SK, Bukh J. Characterization of hepatitis C virus recombinants with chimeric E1/E2 envelope proteins and identification of single amino acids in the E2 stem region important for entry. Journal of Virology 2013; 87: 1385-99.
12. Prentoe J, Serre SB, Ramirez S, Nicosia A, Gottwein JM, Bukh J. Hypervariable region 1 deletion and required adaptive envelope mutations confer decreased dependency on scavenger receptor class B type I and low-density lipoprotein receptor for hepatitis C virus. Journal of Virology 2014; 88: 1725-39.
13. Ramirez S, Li YP, Jensen SB, Pedersen J, Gottwein JM, Bukh J. Highly efficient infectious cell culture of three hepatitis C virus genotype 2b strains and sensitivity to lead protease, nonstructural protein 5A, and polymerase inhibitors. Hepatology 2014; 59: 395-407.
14. Li YP, Ramirez S, Humes D, Jensen SB, Gottwein JM, Bukh J. Differential Sensitivity of 5'UTR-NS5A Recombinants of Hepatitis C Virus Genotypes 1-6 to Protease and NS5A Inhibitors. Gastroenterology 2014; 146: 812-21. 
15. Sølund C, Krarup H, Ramirez S, Thielsen P, Røge BT, Lunding S, Barfod TS, Madsen LG, Tarp B, Christensen PB, Gerstoft J, Laursen AL, Bukh J, Weis N; DANHEP group. Nationwide experience of treatment with protease inhibitors in chronic hepatitis C patients in Denmark: identification of viral resistance mutations. PLoS One 2014; 9: e113034.
16. Li YP^#, Ramirez S^#, Mikkelsen L, Bukh J. Efficient infectious cell culture systems of the hepatitis C virus (HCV) prototype strains HCV-1 and H77. Journal of Virology 2015; 89: 811-23. # Equal contribution.
17. Jensen SB, Serre SB, Humes DG, Ramirez S, Li YP, Bukh J, Gottwein JM. Substitutions at NS3 Residue 155, 156, or 168 of Hepatitis C Virus Genotypes 2 to 6 Induce Complex Patterns of Protease Inhibitor Resistance. Antimicrobial Agents and Chemotherapy 2015; 59: 7426-36 
18. Perez-Del-Pulgar S, Gregori J, Rodríguez-Frias F, González P, García-Cehic D, Ramirez S, Casillas R, Domingo E, Esteban JI, Forns X, Quer J. Quasispecies dynamics in hepatitis C liver transplant recipients receiving grafts from hepatitis C virus infected donors. Journal of General Virology 2015; 96: 3493-8.
19. Serre SB, Jensen SB, Ghanem L, Humes DG, Ramirez S, Li YP, Krarup H, Bukh J, Gottwein JM. Hepatitis C Virus Genotype 1-6 Protease Inhibitor Escape Variants: In Vitro Selection, Fitness and Resistance Patterns in the Context of the Infectious Viral Life Cycle. Antimicrobial Agents and Chemotherapy 2016; 60: 3563-78 
20. Ramirez S, Mikkelsen, Gottwein JM, Bukh J. Robust HCV Genotype 3a Cell-Culture Systems and Sofosbuvir Escape Variants with Drug Resistance and High Viral Fitness. Gastroenterology 2016; 151: 973–85.
21. Pham LV, Ramirez S, Carlsen TH, Li YP, Gottwein JM, Bukh J. Efficient hepatitis C virus genotype 1b Core-NS5A recombinants permit efficacy testing of protease and NS5A inhibitors. Antimicrobial Agents and Chemotherapy 2017 May 24;61(6).
22. Gottwein J, Pham LV, Mikkelsen L, Ghanem L, Ramirez S, Scheel TK, Carlsen TH, Bukh J. Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1-7 and Escape Variants. Gastroenterology. 2018 Apr;154(5):1435-1448.
23. Pham LV, Ramirez S, Gottwein JM, Fahnøe U, Li YP, Pedersen J, Bukh J. HCV Genotype 6a Escape from and Resistance to Velpatasvir, Pibrentasvir, and Sofosbuvir in Robust Infectious Cell Culture Models. Gastroenterology. 2018 Feb 15. pii: S0016-5085(18)30212-9.
24. Humes D, Ramirez S, Jensen TB, Li YP, Gottwein JM, Bukh J. Recombinant hepatitis C virus genotype 5a infectious cell culture systems expressing minimal JFH1 NS5B sequences permit polymerase inhibitor studies. Virology. 2018 in press.
25. Mejer N, Fahnøe U, Galli A, Ramirez S, Benfield T, Bukh J. Ribavirin-induced mutagenesis across the complete open reading frame of hepatitis C virus genotypes 1a and 3a. Journal of General Virology. 2018 in press.