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Investigation

Human viruses of the herpesviridae family

Research Lines

Content with Investigacion Virus del papiloma humano .

A) Effect of vaccination on the prevalence and distribution of Human Papillomavirus (HPV) genotypes. HPV vaccination was introduced in Spain in 2007-2008 for the prevention of cervical cancer and other cancers associated with these viral infections. The use of HPV vaccination is expected to lead to a decrease in vaccine genotypes in the population. However, it may also lead to an increase in other non-vaccine genotypes, similar to the change in vaccine serotypes observed in pneumococcal infections. This requires continuous surveillance of genotype frequency and data to monitor the efficacy of the HPV vaccination program.

B) Study of the distribution and dynamics of HPV infections in risk groups. There are some particularly vulnerable groups, some of them difficult to access (sex workers, transgender groups, etc.), in which HPV infections deserve special attention. The prevalence of HPV infection is especially high in people living with HIV and/or among men who have sex with men. Knowledge of the distribution and dynamics of infections is especially interesting in these groups, as they may help to improve current algorithms for the prevention of anogenital cancer.

C) Study of infection by HPV genotypes and their relationship with progression to neoplastic processes. The oncogenic capacity of some HPV genotypes and their involvement in the production of anogenital cancer is well known. In addition, there are other oncological processes, such as non-melanoma skin cancer, in which HPV could be implicated. Thus, members of the gamma-24 HPV species have recently been associated with skin cancer. It is to be hoped that the appearance of new genotypes and the performance of more extensive studies may lead to the identification of new associations between HPV and neoplastic processes.

D) Study of co-infections by different HPV genotypes. The presence of co-infections of different HPV genotypes is a very frequent finding, both in skin samples and in different mucous membranes. The great genetic diversity of HPV limits the ability of classical molecular methods to perform a comprehensive detection and study of the genotypes present. However, the use of massive sequencing makes it possible to eliminate some of these biases and to obtain more detailed information on the existing HPV populations, as well as to analyze interactions between the different genotypes.

E) Description of new HPV genotypes/variants. Currently at the International HPV Reference Center (Karolinska Institute, Sweden) more than 220 HPV genotypes are described, distributed in 5 different genera. However, improved molecular detection techniques, as well as the use of massive sequencing, are allowing this number to increase rapidly. The study of new genotypes and variants is essential for the validation and quality control of available diagnostic methods. Similarly, their characterization and the study of possible associations of HPV with pathologies other than those already known is a field of great interest for research.

Research projects

Content with Investigacion Virus del papiloma humano .

Título: Impact of vaccination against Human Papillomavirus in Spain: Studye of the distribution of genotypes and its application in surveillance. Principal Investigator: Horacio Gil. Starting/End dates: 2024-2026. Funding Entity: Acción Estratégica de Salud Intramural (AESI) del Instituto de Salud Carlos III. Project Reference: PI23CIII/00006.

Título: Effect of feminizing therapy on immune response in transgender women. Principal Investigator: Victor Manuel Sánchez Merino. Collaborating Investigator: Horacio Gil. Starting/End dates:2025-2027. Funding Entity: Acción Estratégica de Salud Intramural (AESI) del Instituto de Salud Carlos III. Project Reference: PI24CIII/00031.

Publications

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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 DOI

Molecular 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 DOI

Molecular 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 DOI

Going beyond serology for stratifying the risk of CMV infection in transplant recipients

Navarro D, Fernández-Ruiz M, Aguado JM, Sandonís V, Pérez-Romero P*. Going beyond serology for stratifying the risk of CMV infection in transplant recipients. Rev Med Virol. 2019 Jan;29(1):e2017.

PUBMED DOI

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.

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 DOI

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.

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 DOI

CMV-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 DOI

Two 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 DOI

Applying 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 DOI

Use 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 DOI

Timing 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 DOI

Clinical 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 DOI

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.

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 DOI

What is responsible for a large and unusual outbreak of leishmaniasis in Madrid?

8. Carrillo E, Moreno J, Cruz I. What is responsible for a large and unusual outbreak of leishmaniasis in Madrid? Trends Parasitol. 2013 Dec;29(12):579-80.

PUBMED DOI

HCV 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 DOI

Dynamics 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 DOI

Protein 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 DOI

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.

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 DOI

Hepatitis 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 DOI

rotist 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 DOI

List of staff

Additional Information

Our group is interested in infections caused by the 8 known human herpes, which are very important etiological agents due to the high rates of infection, as well as their morbidity and mortality, especially in situations in which the immune system is immature (pediatric disease), senescent (pathologies in advanced age) or immunocompromised (transplanted).

They form a very heterogeneous group, but once the infection occurs, it persists for life through its latency phases. The pathogenicity of alpha- and beta-herpesviruses is related to primary infection and its recurrences, but in gamma-herpesviruses their main pathogenicity lies in their ability to produce tumors.

The main objective of the group is to respond to the medical problems caused by these infections from a multidisciplinary point of view, which includes virological, immunological and molecular aspects.

At present, the group's specific research objectives focus mainly on two topics:

    Pathogenicity markers in congenital cytomegalovirus disease that modulate the immune system during infection and
    Molecular characterization of the varicella zoster virus in cases of vaccine failure. The group's IP is part as a promoter partner of Spin-off: Virnóstica-ISCIII

Our group is interested in infections caused by the 8 known human herpes, which are very important etiological agents due to the high rates of infection, as well as their morbidity and mortality, especially in situations in which the immune system is immature (pediatric disease), senescent (pathologies in advanced age) or immunocompromised (transplanted).

They form a very heterogeneous group, but once the infection occurs, it persists for life through its latency phases. The pathogenicity of alpha- and beta-herpesviruses is related to primary infection and its recurrences, but in gamma-herpesviruses their main pathogenicity lies in their ability to produce tumors.

The main objective of the group is to respond to the medical problems caused by these infections from a multidisciplinary point of view, which includes virological, immunological and molecular aspects.

At present, the group's specific research objectives focus mainly on two topics:

    Pathogenicity markers in congenital cytomegalovirus disease that modulate the immune system during infection and
    Molecular characterization of the varicella zoster virus in cases of vaccine failure. The group's IP is part as a promoter partner of Spin-off: Virnóstica-ISCIII

The current director of CNM is Dr. José Miguel Rubio Muñoz.

Dr. José Miguel Rubio has a degree in Biological Sciences from the Universidad Autónoma de Madrid (1986) and a PhD in Biological Sciences from the same university (1992). He carried out his doctoral thesis at the Department of Genetics of the Universidad Autónoma de Madrid, as Associate Professor (1988-1989), and at the School of Biology of the University of East Anglia in Norwich, UK, as Senior Research Assistant (1989-1992).

During his postdoctoral period he obtained a grant from the European Commission within the Human Capital and Mobility Program to be carried out at the University of “La Sapienza” in Rome, Italy and the Institute of Molecular Biology and Biotechnology in Crete, Greece (1993-1994). Subsequently, he made a further stay funded by the WHO and the university itself at the Department of Entomology, Wageningen University, The Netherlands (1994-1996).

Since 1997 he has been a member of the Instituto de Salud Carlos III (ISCIII), where he joined the Department of Parasitology of the National Center of Microbiology, as an EU-INCO postdoctoral fellow and later with a grant from the Autonomous Community of Madrid (CAM). She was part of the founding group of the National Center for Tropical Medicine (2003-2006) and of the 24/7 Alerts and Emergencies Unit (2006-2018) and is currently Head of the Malaria and Emerging Parasitosis Unit of the National Microbiology Center and is part, as research staff, of the Center for Biomedical Research Network on Infectious Diseases (CIBERINFEC/ISCIII).

During his scientific career he has been Visiting Scientist at the Leonidas e Marie Dean Center (FIOCRUZ-AMAZONAS, Manaus, Brazil) and is an External Consultant of the Parasitology Departments of Cairo University (Egypt) and the Medical Research Center (MRC) of Kuala Lumpur (Malaysia).  He also belongs or has belonged to different national and international committees:  Member of the expert group for malaria control of the European Centre for Disease Control (ECDC) since 2011; Expert-Evaluator for health programs of the European Commission since 2004; Spanish Representative (commissioned by ISCIII and MSC) in the Technical Scientific Committee of the TDR (WHO) 2007-2008; Spanish Deputy Focal Point for microbiology at the European Centre for Disease Control (ECDC) from 2012 to 2020; and, member of the Research Ethics Committee of ISCIII until 2019.

In this period he has published more than 100 articles in international indexed journals, 10 book chapters and has been co-editor of two books in the area of malaria, tropical medicine and neglected diseases. He has participated in 58 competitively funded research projects, 20 of them international, having been the principal investigator in 8 national and 11 international projects as PI of the project or WP leader. In addition, he has led five agreements with companies. Currently he has been awarded four sexenios of research, being presented this year 2025 to the fifth. In the teaching field, he participates in different postgraduate programs in the areas of microbiology and parasitology, having directed seven doctoral theses and more than 20 Master's or Degree final projects, both nationally and internationally. ​​​​​

El laboratorio de Referencia e Investigación en Resistencia a Antibióticos ofrece una amplia cartera de servicios al Sistema Nacional de Salud, las cuales pueden solicitarse en cnm-laboratorios.isciii.es. Jefe del Laboratorio: Jesús Oteo Iglesias (Punto focal Nacional de Resistencia antibiótica).

Dispone de dos programas de Vigilancia oficiales y gratuitos que engloban los ensayos ofertados ya sea como aislamientos individuales o mediante estudio de brotes. El Laboratorio utiliza asimismo técnicas de PCR en tiempo real para la detección de genes de resistencia, estas técnicas se han adaptado a un formato multiplex que permite detectar varios genes en la misma reacción. En los últimos años se han incluido metodologías basadas en la secuenciación de genomas completos para el análisis de bacterias multiresistentes (WGS).

Programa de vigilancia de Haemophilus influenzae. Responsables: María Pérez Vázquez (Punto focal Nacional de Haemophilus influenzae) y Belén Aracil. Laboratorio encargado de la identificación, estudio de sensibilidad y análisis genotípico de aislados de Haemophilus influenzae, centrándose esencialmente en la patología invasiva debida este patógeno. 

Programa de vigilancia de Resistencia a Antibióticos. Responsables: María Pérez Vázquez  y Belén Aracil (Punto focal Nacional de Resistencia antibiótica). Laboratorio encargado de la identificación, el estudio de sensibilidad antibiótica, y el diagnóstico fenotípico y genotípico de los diferentes mecanismos de resistencia a antibióticos fundamentalmente en enterobacterias y gram-negativos no fermentadores y Enterococcus spp.

Estudio de brotes. Responsables: Belén Aracil y María Pérez Vázquez. El programa incluye la caracterización de brotes nosocomiales y clones emergentes de alto riesgo mediante diferentes técnicas moleculares (tabla resumen). Éstas, nos permiten realizar estudios filogenéticos con el fin de obtener una información detallada acerca la relación entre los diferentes aislados y su trazabilidad. El objetivo final es generar datos que se transfieren a los hospitales como ayuda para la prevención o control de la propagación del brote.

Acreditación y Calidad. Responsable: Belén Aracil. El laboratorio Referencia e Investigación en Resistencia a Antibióticos ha sido de los primeros en el ISCIII en la utilización de técnicas acreditadas por la Entidad Nacional de Acreditaciones (ENAC). Este laboratorio consiguió la primera acreditación homologada de técnicas diagnósticas en 2012, programa que ha sido ampliado, de manera que en la actualidad más de la mitad de las técnicas ofrecidas al Sistema Nacional de Salud están debidamente acreditadas por ENAC.

Técnicos responsables de las técnicas realizadas en el Laboratorio: Noelia Lara Fuella y Verónica Bautista Sánchez.

En la siguiente imagen se resumen las técnicas ofrecidas al Sistema Nacional de Salud.

PROGRAMAS NOMBRE CARTERA SERVICIO PATÓGENO DETERMINACIÓN, DETECCIÓN, ANÁLISIS MÉTODOS

Programa de vigilancia de Haemophilus

Programa de vigilancia de resistencia a antibióticos.

Identificación bacteriana

Haemophilus sp.

Enterobacterias, gram-negativos no fermentadores, Enterococcus spp

Identificación bacteriana

Bioquímicos

MALDI TOF

Secuenciación de RNAr

Identificación capsular

Haemophilus influenzae

 

Identificación capsular fenotípica y genotípica

Aglutinación serológica en latex

PCR ind/multiplex

Determinación de Sensibilidad

Haemophilus sp.

Enterobacterias, gram-negativos no fermentadores, Enterococcus

 

Determinación de Sensibilidad

Microdilución                

Tiras epsilon               

Kirby Bauer

Métodos fenotípicos de detección de mecanismos de resistencia

Enterobacterias, gram-negativos no fermentadores,

 

Métodos fenotípicos de detección de mecanismos de resistencia

Discos y tabletas combinados con inhibidores                

Tiras combinadas     

Test de Hodge modificado

CabaNP                               

Inmunocromatografía CBP

Métodos genotípicos de detección de mecanismos de resistencia

Haemophilus sp.

Enterobacterias, gram-negativos no fermentadores, Enterococcus

 

ADN, PCR y secuenciación

PCR ind/multiplex

Análisis comparativo de las secuencias

Tipificación molecular/análisis filogenéticos

Haemophilus sp.

Enterobacterias, gram-negativos no fermentadores, Enterococcus

 

Corte enzimas de restricción, electroforesis

ADN, PCR y secuenciación

Preparación de librerías y secuenciación y análisis de genomas completos

 

PFGE

 

MLST

 

WGS