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Investigation
Organ Transplant
Research Lines
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Research
The Molecular Virology group focuses its research on the study of HIV-1 genetic variation and viral evolution using both in vitro and ex vivo approaches, structured around the following research lines:
- Non-progressor patients. These patients maintain control of the disease in the absence of antiretroviral therapy and have therefore been proposed as a model of functional cure. Our objective is to study the contribution of viral factors to disease control through biological characterization and analysis of viral evolution in individuals with undetectable viral loads (elite controllers, EC), compared with individuals showing other patterns of viral control.
- Viral envelope. This viral protein is key in determining viral fitness. Therefore, its functionality significantly affects infection progression. In collaboration with Dr. Blanco and Dr. Valenzuela, we study which specific events (CD4 binding, fusogenicity, etc.) are associated with envelope functionality. To this end, we have analyzed envelopes from individuals with different patterns of disease progression. Some of these have been contributed to the AIDS Research Network envelope biobank for broader use.
- Dual infection. Infection with more than one viral variant (either through co-infection or superinfection) may have consequences for infection pathogenesis. Within our group, different aspects of DI have been analyzed, including its detection in non-progressor patients, its prevalence and incidence in Spain, and its influence on the neutralizing antibody response.
- Molecular Epidemiology. The group has analyzed viral evolution throughout the epidemic in Spain and in other countries (the Netherlands, Italy, Germany, Uruguay, Panama, Brazil, etc.).
- Role of amino acid residues in reverse transcriptase. We study the role of specific amino acid residues in HIV-1 reverse transcriptase in enzymatic function and replication capacity using an infectious molecular clone previously obtained by the group.
- “In vitro” variability. Serial passage studies have been used to detect the mechanisms responsible for the gain or loss of viral fitness.
- Antiviral studies. We have analyzed the selection of resistance mutations in vitro against different antivirals, as well as the effect of these mutations on viral fitness, and the activity of new antivirals such as ATR inhibitors.
Virological Diagnosis and Reference in HIV and HTLV Infections
The research group provides diagnostic and reference activities through the service portfolio of the National Center for Microbiology to the entire Spanish National Health System.
These services include:
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Diagnosis and reference of HIV infection (types 1 and 2) through detection of specific antibodies and detection of proviral DNA by PCR.
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Diagnosis and reference of HTLV-I/II infection through detection of specific antibodies and detection of proviral DNA by PCR. Quantification of HTLV-1 proviral load by real-time PCR.
European Union Reference Laboratory (EURL) in the field of in vitro diagnostic medical devices for microbiological diagnosis (IVD) of HIV and HTLV (Regulation 2023/2713 of December 5th, 2023). Our role is to confirm the reliability and effectiveness of devices for detecting these pathogens and to ensure their specific performance requirements through laboratory testing before they can be marketed within the European Union.
Research projects
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- Towards a functional cure: Implications of early antiretroviral therapy and hormonal changes on the HIV reservoir in perinatally infected adolescents. Health Research Fund (FIS) – Carlos III Health Institute (01/01/2026 – 31/12/2028). €72,000. PI: María Pernas, Concepción Casado.
- Determination of factors associated with protection against Human Immunodeficiency Virus type 1 reinfection: Identification of correlates of protection. 9th Gilead Fellowship Program for Biomedical Research, Gilead Sciences, S.L. (01/07/2023 – 30/06/2025). €16,330. PI: María Pernas.
- Impact of the envelope on HIV viral replication: New avenues for vaccine development. Health Research Fund (FIS) – Carlos III Health Institute (01/01/2020 – 31/12/2023). €53,000. PI: María Pernas, Concepción Casado.
- Study of HIV-1 virulence in recently infected patients and its contribution, together with clinical and epidemiological factors, to disease progression. Ministry of Economy and Competitiveness. State Program for Scientific and Technical Research and Innovation (30/12/2016 – 30/06/2021). €145,000. PI: Concepción Casado, Cecilio López-Galíndez.
-Contribution of HIV-1 dual infection to virological and clinical evolution in homo/bisexual men. Health Research Fund (FIS) – Carlos III Health Institute (01/01/2014 – 31/01/2016). €74,410. PI: Cecilio López-Galíndez.
- Characterization of non-pathogenic HIV variants obtained “ex vivo” and “in vitro” for the study of disease pathogenesis. Ministry of Science and Innovation (01/01/2011 – 31/01/2014). €169,400. PI: Cecilio López-Galíndez.
- Spanish AIDS Research Network (RIS-RETIC). Carlos III Health Institute (02/01/2017 – 02/01/2022). €195,212. PI: Cecilio López-Galíndez, Concepción Casado.
Publications
Outbreak of brainstem encephalitis associated with enterovirus-A71 in Catalonia, Spain (2016): a clinical observational study in a children’s reference centre in Catalonia
6. D Casas-Alba, M de Sevilla, A Valero-Rello, C Fortuny, JJ Garcia, C Ortez, J Muchart, T Armangue, I Jordan, C Luaces-Cubells, I Barrabeig, R González-Sanz, M Cabrerizo, C Munoz-Almagro, C Launes. Outbreak of brainstem encephalitis associated with enterovirus-A71 in Catalonia, Spain (2016): a clinical observational study in a children’s reference centre in Catalonia. Clin Microbiol Infect 23: 874-881 (2017)
PUBMED DOIMolecular epidemiology of enterovirus and parechovirus infections according to patient age over a 4-year period in Spain.
7. M Cabrerizo*, M Díaz-Cerio, C Muñoz-Almagro, N Rabella, D Tarragó, MP Romero, MJ Pena, C Calvo, S Rey-Cao, A Moreno-Docón, I Martínez-Rienda, A Otero, G Trallero. Molecular epidemiology of enterovirus and parechovirus infections according to patient age over a 4-year period in Spain. J Med Virol 89: 435-442 (2017).
PUBMED DOIMolecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth disease in Spain
9. M Cabrerizo*, D Tarragó, C Muñóz-Almagro, E del Amo, M Domínguez-Gil, JM Eiros, I López-Miragaya, C Pérez, J Reina, A Otero, I González, JE Echevarría, G Trallero. Molecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth diease in Spain. Clin Microbiol Infect; 20: O150–O156 (2014).
PUBMED DOIImpact of pretransplant CMV-specific T-cell immune response in the control of CMV infection after solid organ transplantation: a prospective cohort study. Clin Microbiol Infect.
Molina-Ortega A, Martín-Gandul C, Mena-Romo JD, Rodríguez-Hernández MJ, Suñer M, Bernal C, Sánchez M, Sánchez-Céspedes J, Pérez Romero P*, Cordero E. Impact of pretransplant CMV-specific T-cell immune response in the control of CMV infection after solid organ transplantation: a prospective cohort study. Clin Microbiol Infect. 2019 Jun;25(6):753-758.
PUBMED DOIKinetic of the CMV-specific T-cell immune response and CMV infection in CMV-seropositive kidney transplant recipients receiving rabbit anti-thymocyte globulin induction therapy: A pilot study.
Martín-Gandul C, Pérez-Romero P*, Mena-Romo D, Molina-Ortega A, González-Roncero FM, Suñer M, Bernal G, Cordero E; Spanish Network for Research in Infectious Diseases (REIPI). Kinetic of the CMV-specific T-cell immune response and CMV infection in CMV-seropositive kidney transplant recipients receiving rabbit anti-thymocyte globulin induction therapy: A pilot study. Transpl Infect Dis. 2018 Jun;20(3):e12883.
PUBMED DOICMV-specific T-cell immunity in solid organ transplant recipients at low risk of CMV infection. Chronology and applicability in preemptive therapy.
Mena-Romo JD, Pérez Romero P*, Martín-Gandul C, Gentil MÁ, Suárez-Artacho G, Lage E, Sánchez M, Cordero E. CMV-specific T-cell immunity in solid organ transplant recipients at low risk of CMV infection. Chronology and applicability in preemptive therapy. J Infect. 2017 Oct;75(4):336-345.
PUBMED DOITwo Doses of Inactivated Influenza Vaccine Improve Immune Response in Solid Organ Transplant Recipients: Results of TRANSGRIPE 1-2, a Randomized Controlled Clinical Trial.
Cordero E, Roca-Oporto C, Bulnes-Ramos A, Aydillo T, Gavaldà J, Moreno A, Torre-Cisneros J, Montejo JM, Fortun J, Muñoz P, Sabé N, Fariñas MC, Blanes-Julia M, López-Medrano F, Suárez-Benjumea A, Martinez-Atienza J, Rosso-Fernández C, Pérez-Romero P*. Two Doses of Inactivated Influenza Vaccine Improve Immune Response in Solid Organ Transplant Recipients: Results of TRANSGRIPE 1-2, a Randomized Controlled Clinical Trial. Clin Infect Dis. 2017 Apr 1;64(7):829-838.
PUBMED DOIApplying lessons learned from cytomegalovirus infection in transplant patients to vaccine design.
Blanco-Lobo P, Bulnes-Ramos Á, McConnell MJ, Navarro D, Pérez-Romero P*. Applying lessons learned from cytomegalovirus infection in transplant patients to vaccine design. Drug Discov Today. 2016 Apr;21(4):674-81.
PUBMED DOIUse of antibodies neutralizing epithelial cell infection to diagnose patients at risk for CMV Disease after transplantation.
Blanco-Lobo P, Cordero E, Martín-Gandul C, Gentil MA, Suárez-Artacho G, Sobrino M, Aznar J, Pérez-Romero P*. Use of antibodies neutralizing epithelial cell infection to diagnose patients at risk for CMV Disease after transplantation. J Infect. 2016 May;72(5):597-607.
PUBMED DOITiming of CMV-specific effector memory T cells predicts viral replication and survival after allogeneic hematopoietic stem cell transplantation.
Espigado I, de la Cruz-Vicente F, BenMarzouk-Hidalgo OJ, Gracia-Ahufinger I, Garcia-Lozano JR, Aguilar-Guisado M, Cisneros JM, Urbano-Ispizua A, Perez-Romero P*. Timing of CMV-specific effector memory T cells predicts viral replication and survival after allogeneic hematopoietic stem cell transplantation. Transpl Int. 2014 Dec;27(12):1253-62.
PUBMED DOIClinical impact of neutropenia related with the preemptive therapy of CMV infection in solid organ transplant recipients.
Martín-Gandul C, Pérez-Romero P*, González-Roncero FM, Berdaguer S, Gómez MA, Lage E, Sánchez M, Cisneros JM, Cordero E; Spanish Network for Research in Infectious Diseases REIPI. Clinical impact of neutropenia related with the preemptive therapy of CMV infection in solid organ transplant recipients. J Infect. 2014 Nov;69(5):500-6.
PUBMED DOIViral load, CMV-specific T-cell immune response and cytomegalovirus disease in solid organ transplant recipients at higher risk for cytomegalovirus infection during preemptive therapy.
Martín-Gandul C, Pérez-Romero P*, Blanco-Lobo P, Benmarzouk-Hidalgo OJ, Sánchez M, Gentil MA, Bernal C, Sobrino JM, Rodríguez-Hernández MJ, Cordero E; Spanish Network for Research in Infectious Diseases (REIPI). Viral load, CMV-specific T-cell immune response and cytomegalovirus disease in solid organ transplant recipients at higher risk for cytomegalovirus infection during preemptive therapy. Transpl Int. 2014 Oct;27(10):1060-8.
PUBMED DOIHCV eradication with IFN-based therapy does not completely restore gene expression in PBMCs from HIV/HCV-coinfected patients.
9. Brochado O, Martínez I (*), Berenguer J, Medrano L, González-García J, Jiménez-Sousa MA, Carrero A, Hontañón V, Navarro J, Guardiola JM, Pérez-Latorre L, Micán R, Fernández-Rodríguez A (‡), Resino S (* ‡). HCV eradication with IFN-based therapy does not completely restore gene expression in PBMCs from HIV/HCV-coinfected patients. J Biomed Sci 2021; 28:23 (A; FI= 12.77; D1, Medicine, Research & Experimental; JCR 2021).
PUBMED DOIDynamics of HIV Reservoir and HIV-1 Viral Splicing in HCV-Exposed Individuals after Elimination with DAAs or Spontaneous Clearance.
Martínez-Román P, Crespo-Bermejo C, Valle-Millares D, Lara-Aguilar V, Arca-Lafuente S, Martín-Carbonero, Ryan P, De los Santos I, López-Huertas MR, Palladino C, Muñoz-Muñoz M, Fernández-Rodríguez A*, Coiras M, Briz V, on behalf of COVIHEP network. Dynamics of HIV Reservoir and HIV-1 Viral Splicing in HCV-Exposed Individuals after Elimination with DAAs or Spontaneous Clearance. Journal of Clinical Medicine 2022, 11: 3579.
PUBMED DOIProtein Saver® cards: the best alternative for DBS storage at room temperature for HCV RNA.
Arca-Lafuente S, Casanueva-Benítez C, Crespo-Bermejo C, Lara-Aguilar V, Martín-Carbonero L, De los Santos I, Madrid R, Briz V*. Protein Saver® cards: the best alternative for DBS storage at room temperature for HCV RNA. 903 Scientific Report 2022, 12: 10124.
PUBMED DOIDiarrhoea-causing enteric protist species in intensively and extensively raised pigs (Sus scrofa domesticus) in Southern Spain. Part II: Association with Hepatitis E virus susceptibility.
Rivero-Juarez A, Dashti A, Santín M, George, Köster PC, Lopez-Lopez P, Risalde MA, García-Bocanegra I, Gomez-Villamandos JC, Caballero-Gómez J, Frías M, Bailo B, Ortega S, Muadica AS, Calero-Bernal R, González-Barrio D, Rivero A, Briz V*, Carmena D. Diarrhoea-causing enteric protist species in intensively and extensively raised pigs (Sus scrofa domesticus) in Southern Spain. Part II: Association with Hepatitis E virus susceptibility. Transboundary and Emerging Diseases 2021, 69: e1172-e1178.
PUBMED DOIHepatitis C virus influences HIV-1 viral splicing in coinfected patients.
Martínez-Román P, López-Huertas MR, Crespo-Bermejo C, Arca-Lafuente S, Cortegano I, Valle-Millares D, Gaspar ML, Martín-Carbonero, Domínguez-Domínguez L, Ryan P, De los Santos I, De la Fuente Moral S, Fernández-Rodríguez A, Coiras M, Briz V, on behalf of COVIHEP. Hepatitis C virus influences HIV-1 viral splicing in coinfected patients. J Clin Med 2020, 9 (7): 2091.
PUBMED DOIrotist enteroparasites in wild boar (Sus scrofa ferus) and black Iberian pig (Sus scrofa domesticus) in southern Spain: a protective effect on hepatitis E acquisition?
Rivero-Juárez A, Dashti A, López-López P, Salimo Muadica A, Risalde MA, Köster PC, Machuca I, Bailo B, Hernández de Mingo M, Dacal E, García-Bocanegra I, Saugar JM, Calero-Bernal R, González-Barrio D, Rivero A, Briz V, Carmena D. Protist enteroparasites in wild boar (Sus scrofa ferus) and black Iberian pig (Sus scrofa domesticus) in southern Spain: a protective effect on hepatitis E acquisition? Parasites & Vectors 2020, 13: 281
PUBMED DOIContent with Investigacion .
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Leticia Bernal Martínez
Staff Scientist
ORCID code: 0000-0002-1694-5522
Dr. Bernal-Martínez obtained her degree in Biochemistry from the University of Zaragoza in 2005. She joined the Mycology Reference and Research Laboratory (LRIM) in 2006 under a trainee contract and completed her PhD within the Official Doctoral Program in Microbiology and Parasitology at the Complutense University of Madrid, defending her thesis in 2010 with highest honors (Cum Laude). In 2007, she continued her research activity at LRIM within the framework of the Spanish Network for Research in Infectious Diseases (REIPI). In 2016, she completed a Postgraduate Diploma in Promotion and Management of International Projects (Technical University of Madrid) and undertook a research stay at the Microbiology and Infection Research Domain, Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho (Braga, Portugal). She was subsequently appointed as a PhD researcher within the Biomedical Research Networking Center in Infectious Diseases (CIBERINFEC). Since 2024, she serves as Specialist Scientist at the Carlos III Health Institute (ISCIII) and is responsible for the Diagnostic and Serology Section for Endemic Fungi at the Mycology Reference and Research Laboratory.
Dr. Bernal-Martínez has authored more than 30 peer-reviewed scientific publications and two book chapters. She has actively participated in over 12 research projects and has presented her work at numerous national and international scientific conferences. Her research has focused on human fungal infections, antifungal resistance, therapeutic drug monitoring, genetic variants associated with antifungal metabolism, and the identification of predictive biomarkers of invasive fungal infections. However, her primary expertise lies in the diagnostic field, particularly in the design, optimization, and validation of real-time PCR–based methodologies.
She is currently Principal Investigator of a research project aimed at improving current diagnostic techniques for invasive fungal infections, evaluating emerging diagnostic technologies, and studying primary fungal pathogens. A substantial part of her work has been transferred to the Spanish National Health System and to research centers in Latin America. Many of the diagnostic methodologies developed have been incorporated into the official service portfolio of ISCIII. She has collaborated with multiple hospitals through research projects and clinical trials applying these technologies, as well as with the ISCIII spin-off company Micomol S.L.
Dr. Bernal-Martínez has supervised several Master’s and Undergraduate Final Degree Projects from students at the Complutense University of Madrid and the University of Alcalá. She is a member of the teaching staff of the UNED-ISCIII PhD Program in Biomedical Sciences and Public Health and serves as lecturer in the Master’s Program in Public Health and Research in Infectious Diseases at the University of Alcalá. -
Laura Alcázar Fuoli
Research Scientist
Graduated in Biochemistry from the Autonomous University of Madrid and PhD in Biology from the Complutense University of Madrid in 2006. She completed her doctoral thesis at the National Center of Microbiology (CNM) under the direction of Dr. Emilia Mellado, in the study of the synthesis of Ergosterol in Aspergillus fumigatus. In 2012 Laura joined the reference laboratory in mycology with a researcher contract for the “Miguel Servet” program after having worked for three years as an associate researcher at Imperial College London. During that period his research focused on host adaptation mechanisms and virulence factors of A. fumigatus. In 2014 he obtained the position of Senior Scientist of Public Research Organizations carrying out his research work at the CNM.
List of staff
Additional Information
Induction of allograft tolerance remains a goal to be achieved in organ transplantation. Most therapeutic strategies focus on inhibition of the adaptive immune system, but recent data demonstrate that allogeneic recognition of myeloid cells initiates transplant rejection. Therapies targeting myeloid cells “in vivo” represent a potential target to induce immunological tolerance, but remain clinically unexplored.
Our laboratory uses a revolutionary nanoimmunotherapy of high-density lipoprotein (HDL) nanoparticles loaded with rapamycin (mTORi-HDL) that prevents epigenetic modifications associated with trained immunity, a recently discovered functional state of macrophages. Using an experimental mouse transplant model, our results demonstrate that the administration of this immunotherapy with mTORi-HDL prevents the immune response and promotes tolerance to the transplanted organ.
Our laboratory shows a multidisciplinary research approach articulated in three different objectives to evaluate the clinical relevance and therapeutic effects of immunotherapy in preparation for a clinical trial in organ transplantation. The general objectives will be aimed at confirming the identification of trained immunity as a biomarker and analytical value to predict the risk of rejection in transplant patients under three conditions: prolonged periods of ischemic reperfusion (IRI) (objective 1), allosensitization (objective 2) and infection (objective 3).
Induction of allograft tolerance remains a goal to be achieved in organ transplantation. Most therapeutic strategies focus on inhibition of the adaptive immune system, but recent data demonstrate that allogeneic recognition of myeloid cells initiates transplant rejection. Therapies targeting myeloid cells “in vivo” represent a potential target to induce immunological tolerance, but remain clinically unexplored.
Our laboratory uses a revolutionary nanoimmunotherapy of high-density lipoprotein (HDL) nanoparticles loaded with rapamycin (mTORi-HDL) that prevents epigenetic modifications associated with trained immunity, a recently discovered functional state of macrophages. Using an experimental mouse transplant model, our results demonstrate that the administration of this immunotherapy with mTORi-HDL prevents the immune response and promotes tolerance to the transplanted organ.
Our laboratory shows a multidisciplinary research approach articulated in three different objectives to evaluate the clinical relevance and therapeutic effects of immunotherapy in preparation for a clinical trial in organ transplantation. The general objectives will be aimed at confirming the identification of trained immunity as a biomarker and analytical value to predict the risk of rejection in transplant patients under three conditions: prolonged periods of ischemic reperfusion (IRI) (objective 1), allosensitization (objective 2) and infection (objective 3).