Santseharay Ramirez Almeida
  • Source: Scopus
20132024

Research activity per year

Personal profile

Primary fields of research

My research focuses on the study of RNA viruses, where I have made important contributions to the understanding of the adaptive evolution processes leading to antiviral resistance. I pioneered the development of efficient cell culture systems for studying hepatitis C virus (HCV), which have significantly contributed to high impact research. These systems have been critical for groundbreaking studies on antiviral activity and resistance performed by my host program. We showed proof-of-concept that HCV can develop resistance against the nucleotide analog (nuc) sofosbuvir, and that sofosbuvir exhibits a different barrier to resistance depending on the HCV genotype. This and other studies have been a paradigm shift in the field since it was theorized that the high barrier to resistance of sofosbuvir precluded the emergence of resistance. Nucs target conserved domains of viral polymerases which are essential enzymes involved in the replication of all viruses. For RNA viruses, nucs with broad-spectrum activity such as remdesivir are promising tools to combat epidemics and pandemics. One of the most relevant questions about these class of 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 lead a group within the Copenhagen Hepatitis C program (CO-HEP) studying the molecular mechanisms behind breadth of activity and barrier to resistance of broad-spectrum nucs using model viruses from different RNA virus families (Flaviviridae, Coronaviridae, Togaviridae). My goal is that this research can contribute to the development of better antivirals that can address the global challenge of ever evolving viral emerging diseases.

Current research

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

Study of the molecular mechanisms of antiviral activity and resistance of broad-sepctrum nucleotide analogs across RNA viruses

Teaching

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

Course In Immunology And General Microbiology (Modul: 3908-E16), Master in Human Biology, University of Copenhagen. (Since 2017).

 

 

Possible conflicts of interest

None

CV

Education

2010: Ph.D. Faculty of Medicine, University of Barcelona (UB), Spain.

2007: MSc. Microbiology Department, Hospital Clinic, UB.

2004: BSc. in Biotechnology. Autonomous University of Barcelona, Spain.

Work Experience

2017-present: Associate professor. Copenhagen Hepatitis C Program (CO-HEP) at Department of Immunology and Microbiology (ISIM), University of Copenhagen and Department of Infectious Diseases, Hvidovre Hospital (HVH), Denmark. Employed at ISIM. 14 weeks of maternity leave (2021-2022).

2014-2016: Postdoc. CO-HEP. Employed at ISIM.

2009-2014: Postdoc. CO-HEP. Employed at HVH.

2005-2009: Master and Ph.D student. Liver Unit, Hospital Clínic-IDIBAPS, UB.

Publication metrics

Citations: 1586. H-index: 23 (retrieved from Google Scholar September, 2022). 44 peer-reviewed publications. 12 comunications at international conferences. 4 isued/granted patents, 1 patent application.

Other Activities

2009-present: Reviewer for peer-reviewed journals (Gastroenterology, PLoS Pathog, Am J Transplant, J Virology, J Hepatol). 2016-present: Teacher, Virology Course (Øvelseskursus Virologi) for 6th semester medical school students at UCPH. 2017-present: Lecturer, course in Immunology and General Microbiology, Master in Human Biology, UCPH. Member of Danish Society of Virology (DVS) since 2012; Danish Society for Infectious Diseases (DSI) since 2020; American Society for Microbiology (ASM) since 2021.

Awards

Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis' Legat (2021). Contributor. Ministry of Higher Education and Science: grant pool for coronavirus research (2020). Contributor. Region H Research Fond for Medical Research 2019. Contributor. Novo Nordisk Foundation: Distinguished Investigator Grant 2019. Contributor. Danish Council for Independent Research, Medical Sciences 2019. Contributor. A.P. Møller Fond for Medical Research 2018. Stipend for a Ph.D. study from Candys Foundation 2018. Contributor. Danish Council for Independent Research, Medical Sciences, Sapere Aude: DFF-Topforsker 2014. Contributor. Lundbeck Foundation 2012. Contributor. Danish Council for Independent Research, Medical Sciences 2012. Contributor. Individual post-doctoral stipend from the Danish Council for Independent Research, Medical Sciences 2011. Hvidovre Hospital Research Fond 2010. Mobility Fellowship from the European Network for Vigilance against Viral Resistance, VirGIL 2007. Ph.D. stipend from Institut D’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) 2006.

Management and supervision experience

I tutored undergraduate (3) and graduate students (3 Master, 6 Ph.D). Currently I am main supervisor of 3 Ph.D students, I supervise a laboratory technicians and 2 postdocs.

Scientific focus areas

I am currently leading a group at CO-HEP studying broad-spectrum antivirals across different RNA viruses, with the prospect of defining better molecules that can address the global challenge of viral emerging diseases and of antiviral resistance.  

Introductory remarks on publicationslist

LIST OF PUBLICATIONS

Santseharay Ramirez Almeida

Metrics: Citations: 1591. H-index: 23 (retrieved from Google Scholar October, 2022)

Researcher ID: R-9257-2016

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

Scopus Author ID: 26023617700

 

Published manuscripts

  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 Review. Liver Transplantation 2008;14 Suppl 2:S27-35.
  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 L, 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 Jun;154(8):2194-2208.e12.
  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 Sep;522:177-192.
  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 Aug;99(8):1066-1077
  26. Ramirez S, Bukh J. Current status and future development of infectious cell-culture models for the major genotypes of hepatitis C virus: Essential tools in testing of antivirals and emerging vaccine strategies. Review. Antiviral Research. 2018 Jul 27;158:264-287.
  27. Pham L.V, Jensen S.B, Fahnøe U, Pedersen M.S, Qi Tang, Ghanem L, Ramirez S, Humes D, Serre S.B, Schønning K, Bukh J, Gottwein J.M. HCV genotype 1-6 NS3 residue 80 substitutions impact protease inhibitor activity and promote viral escape. Journal of Hepatology. 2019 Mar;70(3):388-397.
  28. Jensen SB, Fahnøe U, Pham LV, Serre SBN, Tang Q, Ghanem L, Pedersen MS, Ramirez S, Humes D, Pihl AF, Filskov J, Sølund CS, Dietz J, Fourati S, Pawlotsky JM, Sarrazin C, Weis N, Schønning K, Krarup H, Bukh J, Gottwein JM. Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants. Hepatology. 2019 Sep;70(3):771-787.
  29. Mejer N, Galli A, Ramirez S, Fahnøe U, Benfield T, Bukh J. Ribavirin Inhibition of Cell-Culture Infectious Hepatitis C Genotype 1-3 Viruses is Strain-Dependent. Virology. 2020 Jan 15;540:132-140.
  30. Ramirez S, Fernandez-Antunez C, Mikkelsen L, Pedersen J, Li YP, Bukh J. In vitro efficacy and barrier to resistance of sofosbuvir/velpatasvir and glecaprevir/pibrentasvir in HCV genotypes 2a, 2b and 2c. Antimicrob Agents Chemother. 2020 Feb 21;64(3):e01888-19.
  31. Ward JC, Bowyer S, Chen S, Fernandes Campos GR, Ramirez S, Bukh J, Harris M. Insights into the unique characteristics of hepatitis C virus genotype 3 revealed by development of a robust sub-genomic DBN3a replicon. J Gen Virol. 2020 Sep 8. doi: 10.1099/jgv.0.001486.
  32. Mejer N, Fahnøe U, Galli A, Ramirez S, Weiland O, Benfield T, Bukh J. Mutations identified in the HCV polymerase of ribavirin treated chronic hepatitis C patients cause resistance and affect viral replication fidelity.Antimicrob Agents Chemother. 2020 Sep 14:AAC.01417-20.
  33. Galli A, Ramirez S, Bukh J. Lipid Droplets Accumulation during Hepatitis C Virus Infection in Cell-Culture Varies among Genotype 1-3 Strains and Does Not Correlate with Virus Replication. Viruses 2021 Feb 28;13(3):389.
  34. Pham LV, Schou-Pedersen M, Fahnøe U, Fernandez-Antunez C, Humes D, Schønning K, Ramirez S, and Bukh J. HCV genome-wide analysis for development of efficient culture systems and unravelling of antiviral resistance in genotype 4. Gut 2021 Apr 8;gutjnl-2020-323585.
  35. Ramirez S, Fernandez-Antunez C, Galli A, Underwood A, Pham LV, Ryberg LA, Feng A, Pedersen M, Mikkelsen L, Belouzard S, Dubuisson J, Sølund C, Weis N, Gottwein J, Fahnøe U, Bukh J. Overcoming culture restriction for SARS-CoV-2 in human cells facilitates the screening of compounds inhibiting viral replication. Antimicrob Agents Chemother. 2021 Apr 26;AAC.00097-21.
  36. Gammeltoft KA, Zhou Y, Duarte Hernandez CR, Galli A, Offersgaard A, Costa R, Pham LV, Fahnøe U, Feng S, Scheel TKH, Ramirez S, Bukh J, Gottwein JM. Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 In Vitro. Antimicrob Agents Chemother. 2021 Aug 17;65(9):e0268020.
  37. Offersgaard A, Duarte Hernandez CR, Pihl AF, Costa R, Venkatesan NP, Lin X, Van Pham L, Feng S, Fahnøe U, Scheel TKH, Ramirez S, Reichl U, Bukh J, Genzel Y, Gottwein JM. SARS-CoV-2 Production in a Scalable High Cell Density Bioreactor. Vaccines (Basel). 2021 Jun 29;9(7):706.
  38. Zhou Y, Gilmore K, Ramirez S, Settels E, Gammeltoft KA, Pham LV, Fahnøe U, Feng S, Offersgaard A, Trimpert J, Bukh J, Osterrieder K, Gottwein JM, Seeberger PH. In vitro efficacy of artemisinin-based treatments against SARS-CoV-2. Sci Rep. 2021 Jul 16;11(1):14571.
  39. Underwood AP, Sølund C, Fernandez-Antunez C, Villadsen SL, Winckelmann AA, Bollerup S, Mikkelsen LS, Sørensen AL, Feng S, Fahnøe U, Lassauniere R, Fomsgaard A, Ramirez S, Weis N, Bukh J. Neutralisation titres against SARS-CoV-2 are sustained 6 months after onset of symptoms in individuals with mild COVID-19. EBioMedicine. 2021 Sep;71:103519.
  40. Smith DA, Fernandez-Antunez C, Magri A, Bowden R, Chaturvedi N, Fellay J, McLauchlan J, Foster GR, Irving WL; STOP-HCV Consortium, Simmonds P, Pedergnana V, Ramirez S, Bukh J, Barnes E, Ansari MA. Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure. Nat Commun. 2021 Oct 20;12(1):6105.
  41. Zhou Y, Gammeltoft KA, Galli A, Offersgaard A, Fahnøe U, Ramirez S, Bukh J, Gottwein JM. Efficacy of Ion-Channel Inhibitors Amantadine, Memantine and Rimantadine for the Treatment of SARS-CoV-2 In Vitro. Viruses. 2021 Oct 15;13(10):2082.
  42. Sølund, C.; Underwood, A.P.; Fernandez-Antunez, C.; Bollerup, S.; Mikkelsen, L.S.; Villadsen, S.L.; Fahnøe, U.; Winckelmann, A.A.; Feng, S.; Nørløv Vinten, C.A.; Dalegaard, M.I.; Vizgirda, G.; Sørensen, A.-L.; Ramirez, S.; Bukh, J.; Weis, N. Analysis of Neutralization Titers against SARS-CoV-2 in Health-Care Workers Vaccinated with Prime-Boost mRNA–mRNA or Vector–mRNA COVID-19. Vaccines 2022, 10, 75.
  43. Fahnøe, U.; Pham, L.V.; Fernandez-Antunez, C.; Costa, R.; Rivera-Rangel, LR.; Galli, A.; Feng, S.;    Mikkelsen, L.M.; Gottwein, JM.; Scheel, TKH.; *Ramirez, S.; *Bukh, J. Versatile SARS-CoV-2 reverse-genetics systems for the study of antiviral resistance and replication. Viruses 2022, 14, 172  *Equal contribution
  44.  Christensen, D.; Polacek, C.; Sheward, D.J.; Hanke, L.; Morro, A.M.; McInerney, G.; Murrell, B.; Hartmann, K.T.; Jensen, H.E.; Jungersen, G.; Illigen, K.; Isling, L.K; Jensen, R.F.; Hansen, J.S.; Rosenkrands, I.; Fernandez-Antunez, C.; Ramirez, S.; Follmann, F.; Bukh, J.; and Pedersen, G.K. Protection against SARS-CoV-2 Transmission by a Parenteral Prime - Intranasal Boost Vaccine Strategy. EBioMedicine. 2022 Oct;84:104248.

 

Patent references

Issued/Granted Patents:

  • HCV full-length infectious cell culture systems and applications thereof. Patent #: 9,382,517 (July 5, 2016). Inventors: Li YP, Ramirez S, Gottwein JM, Scheel TKH, and Bukh J.
  • Novel HCV culture systems and direct-acting antiviral sensitivity. Patent #: 10,106,783 (October 23, 2018). Inventors: Li YP, Ramirez S, Humes D, Gottwein JM, and Bukh J.
  • High-titer HCV full-length genotype 2b infectious cell culture systems and applications thereof. Patent #: 10,106,872 (October 23, 2018). Inventors: Ramirez S, Li YP, Gottwein JM, and Bukh J.
  • Optimized HCV full-length infectious cell culture systems and applications thereof. Patent #: 10,280,404 (May 7, 2019). Inventors: Li YP, Ramirez S, Bukh J

Patent applications:

  • Efficient cell culture system for hepatitis C virus genotype 6a. Inventors: Pham LV, Ramirez S, Gottwein JM, Li YP, Pedersen J, Bukh J.

Keywords

  • Faculty of Health and Medical Sciences
  • Virology
  • Antiviral drugs
  • Resistance
  • Genetics
  • Evolution
  • Adaptation

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