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LINEAS DE INVESTIGACIÓN
Summary research
Dr. Elena Herrera-Carrillo's research focuses on developing innovative genetic and molecular approaches to combat viral infections and advance gene therapy technologies. Her work integrates RNA biology, genome editing, promoter engineering, peptide-based antivirals, and viral vector design to create precise and durable antiviral strategies.
Her group aims to understand and exploit molecular mechanisms of virus-host interactions to develop next-generation therapies capable of achieving long-term, treatment-free viral control. While much of her work targets Humam Immunodeficiency Virus (HIV), her research also extends to other viral pathogens, including SARS-CoV-2 or Human Papilloma Virus (HPV). By combining expertise in CRISPR-Cas systems, RNA interference, and targeted gene delivery, Dr. Herrera-Carrillo develops versatile molecular tools for both therapeutic and diagnostic applications.
GBV-C peptides as natural HIV inhibitors
She investigated the beneficial effects of co-infection with GB virus C (GBV-C) in HIV-1-infected patients. She designed and synthesized peptides derived from the GBV-C envelope proteins E1 and E2, demonstrating their capacity to interfere with HIV-1 fusion and infectivity in a dose-dependent manner. These findings revealed the potential of GBV-C peptides as natural inhibitors of HIV-1.
1. Fernández-Vidal M, Rojo N, Herrera E, Gómara MJ, Haro I. Liposome destabilization induced by synthetic lipopeptides corresponding to envelope and non-structural domains of GBV-C/HGV virus. Conformational requirements for leakage. Biophys Chem. 2008;132(1):55-63. doi: 10.1016/j.bpc.2007.10.009.
2. Herrera E, Gomara MJ, Mazzini S, Ragg E, Haro I. Synthetic peptides of hepatitis G virus (GBV-C/HGV) in the selection of putative peptide inhibitors of the HIV-1 fusion peptide. J Phys Chem B. 2009, 21;113(20):7383-91. doi: 10.1021/jp900707t.
3. Herrera E, Tenckhoff S, Gómara MJ, Galatola R, Bleda MJ, Gil C, Ercilla G, Gatell JM, Tillmann HL, Haro I. Effect of synthetic peptides belonging to E2 envelope protein of GB virus C on human immunodeficiency virus type 1 infection. J Med Chem. 2010, 26;53(16):6054-63. doi: 10.1021/jm100452c.
RNAi-based gene therapy
Dr. Herrera Carrillo developed a combinatorial RNAi-based anti-HIV gene therapy that is currently in pre-clinical tests. RNA interference (RNAi) is highly effective in inhibiting HIV-1 replication by the expression of antiviral short hairpin RNA (shRNA) in stably transduced T-cell lines. For the development of a durable gene therapy that prevents viral escape, she proposed to combine multiple shRNAs against highly conserved regions of the HIV-1 RNA genome.
1. Herrera-Carrillo E, Liu YP, Berkhout B. The impact of unprotected T cells in RNAi-based gene therapy for HIV-AIDS. Mol Ther. 2014;22(3):596-606. doi: 10.1038/mt.2013.280.
2. Herrera-Carrillo E, Berkhout B. The impact of HIV-1 genetic diversity on the efficacy of a combinatorial RNAi-based gene therapy. Gene Ther. 2015;22(6):485-95. doi: 10.1038/gt.2015.11.
AgoshRNAs: A novel RNAi pathway
Building on her RNAi expertise, Dr. Herrera-Carrillo identified and optimized AgoshRNAs, small RNA molecules processed by Argonaute 2 (Ago2) rather than Dicer. These non-canonical RNAi regulators exhibit strong and specific gene-silencing activity and hold promise not only for safe, long-term therapeutic applications against HIV but also as valuable tools to study gene function in organisms such as malaria parasites, which naturally lacks Dicer.
1. Herrera-Carrillo E, Harwig A, Liu YP, Berkhout B. Probing the shRNA characteristics that hinder Dicer recognition and consequently allow Ago-mediated processing and AgoshRNA activity. RNA. 2014 Sep;20(9):1410-8. doi: 10.1261/rna.043950.113.
2. Herrera-Carrillo E, Harwig A, Berkhout B. Toward optimization of AgoshRNA molecules that use a non-canonical RNAi pathway: variations in the top and bottom base pairs. RNA Biol. 2015;12(4):447-56. doi: 10.1080/15476286.2015.1022024.
3. Herrera-Carrillo E, Gao ZL, Harwig A, Heemskerk MT, Berkhout B. The influence of the 5?-terminal nucleotide on AgoshRNA activity and biogenesis: importance of the polymerase III transcription initiation site. Nucleic Acids Res. 2017 Apr 20;45(7):4036-4050. doi: 10.1093/nar/gkw1203.
4. Herrera-Carrillo E, Harwig A, Berkhout B. Silencing of HIV-1 by AgoshRNA molecules. Gene Ther. 2017 Aug;24(8):453-461. doi: 10.1038/gt.2017.44.
5. Hentzschel F, Mitesser V, Fraschka SA, Krzikalla D, Herrera-Carrillo E, Berkhout B, Bártfai R, Mueller AK, Grimm D. Gene knockdown in malaria parasites via non-canonical RNAi. Nucleic Acids Res. 2020 48(1):e2
Promoter engineering and gene expression control
Her group uncovered unexpected RNA polymerase II activity in commonly used RNA polymerase III promoters, such as H1 and U6. This discovery enables simultaneous expression of guide RNAs and larger transgenes from a single compact promoter, offering innovative possibilities for streamlined gene therapy vector design and CRISPR-based applications.
1. Gao Z, Harwig A, Berkhout B, Herrera-Carrillo E*. Mutation of nucleotides around the +1 position of type 3 polymerase III promoters: The effect on transcriptional activity and start site usage. Transcription. 2017;8(5):275-287. doi: 10.1080/21541264.2017.1322170.
2. Gao Z, Herrera-Carrillo E*, Berkhout B. RNA polymerase II activity of type 3 Pol III promoters. Mol Ther Nucleic Acids. 2018 Sep 7;12:135-145. doi: 10.1016/j.omtn.2018.05.001. *corresponding senior author.
3. Gao Z, Herrera-Carrillo E, Berkhout B. A Single H1 Promoter Can Drive Both Guide RNA and Endonuclease Expression in the CRISPR-Cas9 System. Mol Ther Nucleic Acids. 2019 1;14:32-40. doi: 10.1016/j.omtn.2018.10.016.
4. Gao Z, van der Velden YU, Fan M, van der Linden CA, Vink M, Herrera-Carrillo E, Berkhout B. Engineered miniature H1 promoters with dedicated RNA polymerase II or III activity. J Biol Chem. 2021, 296:100026. doi: 10.1074/jbc.RA120.015386.
CRISPR-Cas therapeutic strategies
A major focus of her current research is the application of CRISPR-Cas systems to eliminate HIV proviral DNA. Dr. Herrera-Carrillo and collaborators have designed highly specific Cas12-based antivirals that can neutralize all infectious HIV with a single guide RNA and prevent viral escape using combinatorial CRISPR approaches. These advances mark an important step toward achieving a sterilizing HIV cure.
1. Fan M, Berkhout B and Herrera-Carrillo E. A combinatorial CRISPR-Cas12a attack on HIV DNA. Mol. Ther. Methods and clinical development. 2022, 26;25:43-51
2. Gao Z, Fan M, Das AT, Herrera-Carrillo E* and Berkhout B. Extinction of all infectious HIV in cell culture by the CRISPR-Cas12a system with only a single crRNA. Nucleic Acids Res. 2020 *corresponding senior author
Targeted vector engineering
In collaboration with partners, Dr. Herrera-Carrillo contributes to the engineering of receptor-targeted lentiviral (LV) and adeno-associated (AAV) vectors using paramyxoviral glycoproteins and designed ankyrin repeat proteins (DARPins). This technology enables selective delivery of therapeutic genes to specific target cells, improving the precision and safety of antiviral gene therapie.
1. Riechert V, Hein S, Visser M, Zimmermann M, Wesche J, Adams PA, Theuerkauf SA, Jamali A, Wangorsch A, Reuter A, Pasternak AO, Hartmann J, Greinacher A, Herrera-Carrillo E, Berkhout B, Cichutek K, Buchholz CJ. Fc?RIIA-specific DARPins as novel tools in blood cell analysis and platelet aggregation. J Biol Chem. 2023 Jun;299(6):104743. doi: 10.1016/j.jbc.2023.104743.
2. Theuerkauf SA, Herrera-Carrillo E, John F, Zinser LJ, Molina MA, Riechert V, Thalheimer FB, Börner K, Grimm D, Chlanda P, Berkhout B, Buchholz CJ. AAV vectors displaying bispecific DARPins enable dual-control targeted gene delivery. Biomaterials, 2023;303:122399. doi: 10.1016/j.biomaterials.2023.122399
SARS-CoV-2 research
During the COVID-19 pandemic, Dr. Herrera-Carrillo extended her expertise to coronavirus biology. Her group contributed to the study of SARS-CoV-2 evolution, including the emergence of the Omicron variant, and developed CRISPR-Cas13d-based antiviral and diagnostic tools capable of targeting multiple human coronaviruses.
1. Berkhout B. and Herrera-Carrillo E. SARS-CoV-2 evolution: on the sudden appearance of the Omicron variant. JVI 2022 Apr 13;96(7):e0009022, doi: 10.1128/jvi.00090-22.
2. Hussein M, Andrade dos Ramos Z, Berkhout B and Herrera-Carrillo E. In Silico Prediction and Selection of Target Sequences in the SARS-CoV-2 RNA Genome for an Antiviral Attack. Viruses, 2022 Feb 14;14(2):385. doi: 10.3390/v14020385
3. Hussein M, Andrade dos Ramos Z, Vink MA 1, Kroon P, Yu, Z, Enjuanes L, Zuñiga S, Berkhout B and Herrera-Carrillo E. Efficient CRISPR-Cas13d-Based Antiviral Strategy to Combat SARS-CoV-2. Viruses 2023, 15(3), 686; doi.org/10.3390/v15030686
ORGANISMOS FINANCIADORES ÚLTIMOS 5 AÑOS
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