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Microbial Immunology and Immunogenetics

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:

  • Diagnosis and reference of HIV infection (types 1 and 2) through detection of specific antibodies and detection of proviral DNA by PCR.

  • 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

Content with Investigacion Virología Molecular .

- 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.

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Publications

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Alcazar-Fuoli L, Mellado E, Cuenca-Estrella M, Sanglard D. Probing the role of point mutations in the cyp51A gene from Aspergillus fumigatus in the model yeast Saccharomyces cerevisiae. Med Mycol. 2011 Apr

Alcazar-Fuoli L, Mellado E, Cuenca-Estrella M, Sanglard D. Probing the role of point mutations in the cyp51A gene from Aspergillus fumigatus in the model yeast Saccharomyces cerevisiae. Med Mycol. 2011 Apr;49(3):276-84. doi: 10.3109/13693786.2010.512926. Epub 2010 Sep 10. PMID: 20831364.

PUBMED DOI

Alcazar-Fuoli L, Cuesta I, Rodriguez-Tudela JL, Cuenca-Estrella M, Sanglard D, Mellado E. Three-dimensional models of 14α-sterol demethylase (Cyp51A) from Aspergillus lentulus and Aspergillus fumigatus: an insight into differences in voriconazole interaction. Int J Antimicrob Agents. 2011 Nov

Alcazar-Fuoli L, Cuesta I, Rodriguez-Tudela JL, Cuenca-Estrella M, Sanglard D, Mellado E. Three-dimensional models of 14α-sterol demethylase (Cyp51A) from Aspergillus lentulus and Aspergillus fumigatus: an insight into differences in voriconazole interaction. Int J Antimicrob Agents. 2011 Nov;38(5):426-34. doi: 10.1016/j.ijantimicag.2011.06.005. Epub 2011 Aug 25. PMID: 21871783.

PUBMED DOI

Alcazar-Fuoli L, Mellado E. Ergosterol biosynthesis in Aspergillus fumigatus: its relevance as an antifungal target and role in antifungal drug resistance.

Alcazar-Fuoli L, Mellado E. Ergosterol biosynthesis in Aspergillus fumigatus: its relevance as an antifungal target and role in antifungal drug resistance. Front Microbiol. 2013 Jan 10;3:439. doi: 10.3389/fmicb.2012.00439. PMID: 23335918; PMCID: PMC3541703.

PUBMED DOI

Bernal-Martínez L, Alcazar Fuoli L, Miguel-Revilla B, Carvalho A, Cuétara Garcia MS, Garcia-Rodriguez J, Cunha C, Gómez-García de la Pedrosa E, Gomez-Lopez A. High-Resolution Melting Assay for Genotyping Variants of the CYP2C19 Enzyme and Predicting Voriconazole Effectiveness. Antimicrob Agents Chemother. 2019 May 24

Bernal-Martínez L, Alcazar Fuoli L, Miguel-Revilla B, Carvalho A, Cuétara Garcia MS, Garcia-Rodriguez J, Cunha C, Gómez-García de la Pedrosa E, Gomez-Lopez A. High-Resolution Melting Assay for Genotyping Variants of the CYP2C19 Enzyme and Predicting Voriconazole Effectiveness. Antimicrob Agents Chemother. 2019 May 24;63(6):e02399-18. doi: 10.1128/AAC.02399-18. PMID: 30910893; PMCID:PMC6535561.

PUBMED DOI

Lupiañez CB, Martínez-Bueno M, Sánchez-Maldonado JM, Badiola J, Cunha C, Springer J, Lackner M, Segura-Catena J, Canet LM, Alcazar-Fuoli L, López-Nevot MA, Fianchi L, Aguado JM, Pagano L, López-Fernández E, Alarcón-Riquelme M, Potenza L, Gonçalves SM, Luppi M, Moratalla L, Solano C, Sampedro A, González-Sierra P, Cuenca-Estrella M, Lagrou K, Maertens JA, Lass-Flörl C, Einsele H, Vazquez L; PCRAGA Study Group, Loeffler J, Ríos-Tamayo R, Carvalho A, Jurado M, Sainz J. Polymorphisms within the ARNT2 and CX3CR1 Genes Are Associated with the Risk of Developing Invasive Aspergillosis. Infect Immun. 2020 Mar 23

Lupiañez CB, Martínez-Bueno M, Sánchez-Maldonado JM, Badiola J, Cunha C, Springer J, Lackner M, Segura-Catena J, Canet LM, Alcazar-Fuoli L, López-Nevot MA, Fianchi L, Aguado JM, Pagano L, López-Fernández E, Alarcón-Riquelme M, Potenza L, Gonçalves SM, Luppi M, Moratalla L, Solano C, Sampedro A, González-Sierra P, Cuenca-Estrella M, Lagrou K, Maertens JA, Lass-Flörl C, Einsele H, Vazquez L; PCRAGA Study Group, Loeffler J, Ríos-Tamayo R, Carvalho A, Jurado M, Sainz J. Polymorphisms within the ARNT2 and CX3CR1 Genes Are Associated with the Risk of Developing Invasive Aspergillosis. Infect Immun. 2020 Mar 23;88(4):e00882-19. doi: 10.1128/IAI.00882-19. PMID: 31964743; PMCID: PMC7093133.

PUBMED DOI

Are Reduced Levels of Coagulation Proteins Upon Admission Linked to COVID-19 Severity and Mortality? Front Med (Laussane).

Ceballos FC; Ryan P; Blancas R; et al; Jiménez-Sousa MÁ (20/20). Are Reduced Levels of Coagulation Proteins Upon Admission Linked to COVID-19 Severity and Mortality? Front Med (Laussane). 2021; 8:718053. PMID: 34660629. doi: 10.3389/fmed.2021.718053.

T allele was linked to non-AIDS progression in ART-naïve HIV-infected patients: a retrospective study.

Jiménez-Sousa MA; Jiménez JL; Bellón JM; et al (1/10). CYP27B1 rs10877012 T allele was linked to non-AIDS progression in ART-naïve HIV-infected patients: a retrospective study. J Acquir Immune Defic Syndr 2020 ;85(5):659-664. doi: 10.1097/QAI.0000000000002485.

PBMCs gene expression signature of advanced cirrhosis with high risk for clinically significant portal hypertension in HIV/HCV coinfected patients

Salguero, Sergio; Brochado-Kith, Oscar; Verdices, Ana Virseda; et al; Jiménez-Sousa María A (‡, AC); Resino, Salvador (‡, AC). (12/12). 2023. PBMCs gene expression signature of advanced cirrhosis with high risk for clinically significant portal hypertension in HIV/HCV coinfected patients: A cross-control study. Biomedicine & pharmacotherapy. 159, pp.114220. ISSN 1950-6007.

Relative telomere length impact on mortality of COVID-19: Sex differences.Journal of medical virology.

Virseda-Berdices, Ana; Concostrina-Martinez, Leyre; Martinez-Gonzalez, Oscar; et al; Fernandez-Rodriguez, Amanda (‡), Jiménez-Sousa María A (‡). (14/14). 2023. Relative telomere length impact on mortality of COVID-19: Sex differences.Journal of medical virology. 95-1, pp.e28368. ISSN 1096-9071.

Plasma miRNA profile at COVID-19 onset predicts severity status and mortality.

Fernandez-Pato, Asier; Virseda-Berdices, Ana; Resino, Salvador; et al; Jiménez-Sousa María A (‡, AC); Fernandez-Rodriguez, Amanda (‡). (20/20). 2022. Plasma miRNA profile at COVID-19 onset predicts severity status and mortality. EMERGING MICROBES & INFECTIONS. 11(1):676-688. doi: 10.1080/22221751.2022.2038021.

Blood microbiome is associated with changes in portal hypertension after successful direct-acting antiviral therapy in patients with HCV-related cirrhosis.The Journal of antimicrobial chemotherapy.

Virseda-Berdices, Ana; Brochado-Kith, Oscar; Diez, Cristina; et al; Jimenez-Sousa, Maria Angeles. (16/16). 2021. Blood microbiome is associated with changes in portal hypertension after successful direct-acting antiviral therapy in patients with HCV-related cirrhosis.The Journal of antimicrobial chemotherapy. 77(3):719-726. doi: 10.1093/jac/dkab444. ISSN 1460-2091.

Chronic pulmonary aspergillosis update: A year in review. Med Mycol. 2019 Apr 1

Barac A, Kosmidis C, Alastruey-Izquierdo A, Salzer HJF; CPAnet. Chronic pulmonary aspergillosis update: A year in review. Med Mycol. 2019 Apr 1;57(Supplement_2):S104-S109. doi: 10.1093/mmy/myy070. PMID: 30816975.

PUBMED DOI

Laursen CB, Davidsen JR, Van Acker L, Salzer HJF, Seidel D, Cornely OA, Hoenigl M, Alastruey-Izquierdo A, Hennequin C, Godet C, Barac A, Flick H, Munteanu O, Van Braeckel E. CPAnet Registry-An International Chronic Pulmonary Aspergillosis Registry. J Fungi (Basel). 2020 Jun

Laursen CB, Davidsen JR, Van Acker L, Salzer HJF, Seidel D, Cornely OA, Hoenigl M, Alastruey-Izquierdo A, Hennequin C, Godet C, Barac A, Flick H, Munteanu O, Van Braeckel E. CPAnet Registry-An International Chronic Pulmonary Aspergillosis Registry. J Fungi (Basel). 2020 Jun 29;6(3):E96. doi: 10.3390/jof6030096. PMID: 32610566.

PUBMED DOI

Project from GEMICOMED (SEIMC) and REIPI. Molecular identification and susceptibility testing of molds isolated in a Prospective Surveillance of Triazole Resistance in Spain (FILPOP2 study). Antimicrob Agents Chemother. 2018 Jun

Alastruey-Izquierdo A*, Alcazar-Fuoli L, Rivero-Menéndez O, Ayats J, Castro C, García-Rodríguez J, Goterris-Bonet L, Ibáñez-Martínez E, Linares-Sicilia MJ, Martin-Gomez MT, Martín-Mazuelos E, Pelaez T, Peman J, Rezusta A, Rojo S, Tejero R, Vicente Anza D, Viñuelas J, Zapico MS, Cuenca-Estrella M; members of the FILPOP2 Project from GEMICOMED (SEIMC) and REIPI. Molecular identification and susceptibility testing of molds isolated in a Prospective Surveillance of Triazole Resistance in Spain (FILPOP2 study). Antimicrob Agents Chemother. 2018 Jun 25. doi: 10.1128/AAC.00358-18. PMID: 29941643.

PUBMED DOI

In vitro activity of APX001A against rare moulds using EUCAST and CLSI methodologies. J Antimicrob Chemother. 2019 May 1

Rivero-Menendez O, Cuenca-Estrella M, Alastruey-Izquierdo A.* In vitro activity of APX001A against rare moulds using EUCAST and CLSI methodologies. J Antimicrob Chemother. 2019 May 1;74(5):1295-1299. doi: 10.1093/jac/dkz022. PMID: 30753499.

PUBMED DOI

In vitro activity of olorofim (F901318) against clinical isolates of cryptic species of Aspergillus by EUCAST and CLSI methodologies. J Antimicrob Chemother. 2019 Jun 1

Rivero-Menendez O, Cuenca-Estrella M, Alastruey-Izquierdo A.* In vitro activity of olorofim (F901318) against clinical isolates of cryptic species of Aspergillus by EUCAST and CLSI methodologies. J Antimicrob Chemother. 2019 Jun 1;74(6):1586-1590. doi: 10.1093/jac/dkz078. PMID: 30891600.

PUBMED DOI

Molecular Identification, Antifungal Susceptibility Testing, and Mechanisms of Azole Resistance in Aspergillus Species Received within a Surveillance Program on Antifungal Resistance in Spain. Antimicrob Agents Chemother. 2019 Aug 23

Rivero-Menendez O, Soto-Debran JC, Medina N, Lucio J, Mellado E, Alastruey-Izquierdo A*. Molecular Identification, Antifungal Susceptibility Testing, and Mechanisms of Azole Resistance in Aspergillus Species Received within a Surveillance Program on Antifungal Resistance in Spain. Antimicrob Agents Chemother. 2019 Aug 23;63(9). doi: 10.1128/AAC.00865-19. PMID: 31285229.

PUBMED DOI

Clinical and Laboratory Development of Echinocandin Resistance in Candida glabrata: Molecular Characterization. Front Microbiol. 2019 Jul 11

Rivero-Menendez O, Navarro-Rodriguez P, Bernal-Martinez L, Martin-Cano G, Lopez-Perez L, Sanchez-Romero I, Perez-Ayala A, Capilla J, Zaragoza O, Alastruey-Izquierdo A*. Clinical and Laboratory Development of Echinocandin Resistance in Candida glabrata: Molecular Characterization. Front Microbiol. 2019 Jul 11;10:1585. doi: 10.3389/fmicb.2019.01585. PMID: 31354675.

PUBMED DOI

In vitro activity of olorofim against clinical isolates of Scedosporium species and Lomentospora prolificans using EUCAST and CLSI methodologies. J Antimicrob Chemother. 2020 Aug 28

Rivero-Menendez O, Cuenca-Estrella M, Alastruey-Izquierdo A.* In vitro activity of olorofim against clinical isolates of Scedosporium species and Lomentospora prolificans using EUCAST and CLSI methodologies. J Antimicrob Chemother. 2020 Aug 28. doi: 10.1093/jac/dkaa351. PMID:32856079.

PUBMED DOI

Early innate immune response triggered by the human respiratory syncytial virus and its regulation by ubiquitination/deubiquitination processes.

Martín-Vicente M*, Resino S#, Martínez I#*. Early innate immune response triggered by the human respiratory syncytial virus and its regulation by ubiquitination/deubiquitination processes. J Biomed Sci. 2022 Feb 13;29(1):11. doi: 10.1186/s12929-022-00793-3. PMID: 35152905 (R; FI= 12.771; D1 Medicine, Research & Experimental; JCR 2021).

PUBMED

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