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3. Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19

Author

Varona, Jose F, Landete, Pedro, Lopez-Martin, Jose A, Estrada, Vicente, Paredes, Roger, Guisado-Vasco, Pablo, de Orueta, Lucia Fernandez, Torralba, Miguel, Fortun, Jesus, Vates, Roberto, Barberan, Jose, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemi, Porras, Lourdes, Gijon, Paloma, Monereo, Alfonso, Abad, Daniel, Zuñiga, Sonia, Sola, Isabel, Rodon, Jordi, Vergara-Alert, Julia, Izquierdo-Useros, Nuria, Fudio, Salvador, Pontes, Maria Jose, de Rivas, Beatriz, de Velasco, Patricia Giron, Nieto, Antonio, Gomez, Javier, Aviles, Pablo, Lubomirov, Rubin, Belgrano, Alvaro, Sopesen, Belen, White, Kris M, Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin, Thorne, Lucy G, Jolly, Clare, Towers, Greg J, Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, McGovern, Briana L, Rodriguez, M Luis, Enjuanes, Luis, Fernandez-Sousa, Jose M, Krogan, Nevan J, Jimeno, Jose M, and Garcia-Sastre, Adolfo

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Infectious Diseases, Cancer, Lung, Clinical Trials and Supportive Activities, Patient Safety, Prevention, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being, Adult, Aged, COVID-19, Cell Line, Tumor, Depsipeptides, Drug Evaluation, Preclinical, Female, Hospitalization, Humans, Kaplan-Meier Estimate, Length of Stay, Male, Middle Aged, Neutropenia, Peptides, Cyclic, SARS-CoV-2, Treatment Outcome, Viral Load, COVID-19 Drug Treatment, Biological sciences, Biomedical and clinical sciences
Abstract

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.

Published
2022

4. Evolution of enhanced innate immune evasion by SARS-CoV-2

Author

Thorne, Lucy G, Bouhaddou, Mehdi, Reuschl, Ann-Kathrin, Zuliani-Alvarez, Lorena, Polacco, Ben, Pelin, Adrian, Batra, Jyoti, Whelan, Matthew VX, Hosmillo, Myra, Fossati, Andrea, Ragazzini, Roberta, Jungreis, Irwin, Ummadi, Manisha, Rojc, Ajda, Turner, Jane, Bischof, Marie L, Obernier, Kirsten, Braberg, Hannes, Soucheray, Margaret, Richards, Alicia, Chen, Kuei-Ho, Harjai, Bhavya, Memon, Danish, Hiatt, Joseph, Rosales, Romel, McGovern, Briana L, Jahun, Aminu, Fabius, Jacqueline M, White, Kris, Goodfellow, Ian G, Takeuchi, Yasu, Bonfanti, Paola, Shokat, Kevan, Jura, Natalia, Verba, Klim, Noursadeghi, Mahdad, Beltrao, Pedro, Kellis, Manolis, Swaney, Danielle L, García-Sastre, Adolfo, Jolly, Clare, Towers, Greg J, and Krogan, Nevan J

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Immunology, Medical Microbiology, Genetics, Emerging Infectious Diseases, Infectious Diseases, Coronaviruses, 2.1 Biological and endogenous factors, Aetiology, Infection, COVID-19, Coronavirus Nucleocapsid Proteins, Evolution, Molecular, Humans, Immune Evasion, Immunity, Innate, Interferons, Mitochondrial Precursor Protein Import Complex Proteins, Phosphoproteins, Phosphorylation, Proteomics, RNA, Viral, RNA-Seq, SARS-CoV-2, General Science & Technology
Abstract

The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6-all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection4. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants.

Published
2022

7. SARS-CoV-2 variants evolve convergent strategies to remodel the host response

Author

Bouhaddou, Mehdi, Reuschl, Ann-Kathrin, Polacco, Benjamin J., Thorne, Lucy G., Ummadi, Manisha R., Ye, Chengjin, Rosales, Romel, Pelin, Adrian, Batra, Jyoti, Jang, Gwendolyn M., Xu, Jiewei, Moen, Jack M., Richards, Alicia L., Zhou, Yuan, Harjai, Bhavya, Stevenson, Erica, Rojc, Ajda, Ragazzini, Roberta, Whelan, Matthew V.X., Furnon, Wilhelm, De Lorenzo, Giuditta, Cowton, Vanessa, Syed, Abdullah M., Ciling, Alison, Deutsch, Noa, Pirak, Daniel, Dowgier, Giulia, Mesner, Dejan, Turner, Jane L., McGovern, Briana L., Rodriguez, M. Luis, Leiva-Rebollo, Rocio, Dunham, Alistair S., Zhong, Xiaofang, Eckhardt, Manon, Fossati, Andrea, Liotta, Nicholas F., Kehrer, Thomas, Cupic, Anastasija, Rutkowska, Magdalena, Mena, Ignacio, Aslam, Sadaf, Hoffert, Alyssa, Foussard, Helene, Olwal, Charles Ochieng’, Huang, Weiqing, Zwaka, Thomas, Pham, John, Lyons, Molly, Donohue, Laura, Griffin, Aliesha, Nugent, Rebecca, Holden, Kevin, Deans, Robert, Aviles, Pablo, Lopez-Martin, Jose A., Jimeno, Jose M., Obernier, Kirsten, Fabius, Jacqueline M., Soucheray, Margaret, Hüttenhain, Ruth, Jungreis, Irwin, Kellis, Manolis, Echeverria, Ignacia, Verba, Kliment, Bonfanti, Paola, Beltrao, Pedro, Sharan, Roded, Doudna, Jennifer A., Martinez-Sobrido, Luis, Patel, Arvind H., Palmarini, Massimo, Miorin, Lisa, White, Kris, Swaney, Danielle L., Garcia-Sastre, Adolfo, Jolly, Clare, Zuliani-Alvarez, Lorena, Towers, Greg J., and Krogan, Nevan J.

Published
2023
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8. Evasion of cGAS and TRIM5 defines pandemic HIV

Author

Zuliani-Alvarez, Lorena, Govasli, Morten L., Rasaiyaah, Jane, Monit, Chris, Perry, Stephen O., Sumner, Rebecca P., McAlpine-Scott, Simon, Dickson, Claire, Rifat Faysal, K. M., Hilditch, Laura, Miles, Richard J., Bibollet-Ruche, Frederic, Hahn, Beatrice H., Boecking, Till, Pinotsis, Nikos, James, Leo C., Jacques, David A., and Towers, Greg J.

Published
2022
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10. Evolutionary remodelling of N‐terminal domain loops fine‐tunes SARS‐CoV‐2 spike

Author

Cantoni, Diego, Murray, Matthew J, Kalemera, Mphatso D, Dicken, Samuel J, Stejskal, Lenka, Brown, Georgina, Lytras, Spyros, Coey, Jonathon D, McKenna, James, Bridgett, Stephen, Simpson, David, Fairley, Derek, Thorne, Lucy G, Reuschl, Ann‐Kathrin, Forrest, Calum, Ganeshalingham, Maaroothen, Muir, Luke, Palor, Machaela, Jarvis, Lisa, Willett, Brian, Power, Ultan F, McCoy, Laura E, Jolly, Clare, Towers, Greg J, Doores, Katie J, Robertson, David L, Shepherd, Adrian J, Reeves, Matthew B, Bamford, Connor G G, and Grove, Joe

Published
2022
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12. Art and science: not as different as you think

Author

Walter, John, Milne, Richard, and Towers, Greg J.

Abstract

Greg Towers, Professor of Molecular Virology at University College London, and John Walter, Artist, are interviewed by Professor Richard Milne, Head of Teaching in Infection and Immunity at University College London about their science and art collaboration.

Published
2024
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14. Publisher Correction: Evolution of enhanced innate immune evasion by SARS-CoV-2

Author

Thorne, Lucy G., Bouhaddou, Mehdi, Reuschl, Ann-Kathrin, Zuliani-Alvarez, Lorena, Polacco, Ben, Pelin, Adrian, Batra, Jyoti, Whelan, Matthew V. X., Hosmillo, Myra, Fossati, Andrea, Ragazzini, Roberta, Jungreis, Irwin, Ummadi, Manisha, Rojc, Ajda, Turner, Jane, Bischof, Marie L., Obernier, Kirsten, Braberg, Hannes, Soucheray, Margaret, Richards, Alicia, Chen, Kuei-Ho, Harjai, Bhavya, Memon, Danish, Hiatt, Joseph, Rosales, Romel, McGovern, Briana L., Jahun, Aminu, Fabius, Jacqueline M., White, Kris, Goodfellow, Ian G., Takeuchi, Yasu, Bonfanti, Paola, Shokat, Kevan, Jura, Natalia, Verba, Klim, Noursadeghi, Mahdad, Beltrao, Pedro, Kellis, Manolis, Swaney, Danielle L., García-Sastre, Adolfo, Jolly, Clare, Towers, Greg J., and Krogan, Nevan J.

Published
2022
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15. HIV integration targeting: a pathway involving Transportin-3 and the nuclear pore protein RanBP2.

Author

Ocwieja, Karen E, Brady, Troy L, Ronen, Keshet, Huegel, Alyssa, Roth, Shoshannah L, Schaller, Torsten, James, Leo C, Towers, Greg J, Young, John AT, Chanda, Sumit K, König, Renate, Malani, Nirav, Berry, Charles C, and Bushman, Frederic D

Subjects
Humans, HIV, beta Karyopherins, Nuclear Pore Complex Proteins, Molecular Chaperones, RNA, Small Interfering, Virus Replication, Gene Expression Regulation, Viral, gag Gene Products, Human Immunodeficiency Virus, Host-Pathogen Interactions, Gene Knockdown Techniques, HEK293 Cells, Gene Expression Regulation, Viral, RNA, Small Interfering, gag Gene Products, Human Immunodeficiency Virus, Virology, Microbiology, Immunology, Medical Microbiology
Abstract

Genome-wide siRNA screens have identified host cell factors important for efficient HIV infection, among which are nuclear pore proteins such as RanBP2/Nup358 and the karyopherin Transportin-3/TNPO3. Analysis of the roles of these proteins in the HIV replication cycle suggested that correct trafficking through the pore may facilitate the subsequent integration step. Here we present data for coupling between these steps by demonstrating that depletion of Transportin-3 or RanBP2 altered the terminal step in early HIV replication, the selection of chromosomal sites for integration. We found that depletion of Transportin-3 and RanBP2 altered integration targeting for HIV. These knockdowns reduced HIV integration frequency in gene-dense regions and near gene-associated features, a pattern that differed from that reported for depletion of the HIV integrase binding cofactor Psip1/Ledgf/p75. MLV integration was not affected by the Transportin-3 knockdown. Using siRNA knockdowns and integration targeting analysis, we also implicated several additional nuclear proteins in proper target site selection. To map viral determinants of integration targeting, we analyzed a chimeric HIV derivative containing MLV gag, and found that the gag replacement phenocopied the Transportin-3 and RanBP2 knockdowns. Thus, our data support a model in which Gag-dependent engagement of the proper transport and nuclear pore machinery mediate trafficking of HIV complexes to sites of integration.

Published
2011

21. Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), National Institute of Allergy and Infectious Diseases (US), Swiss National Science Foundation, Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Vergara-Alert, Júlia, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, Belgrano, Álvaro, Sopesén, Belén, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin; Thorne, Lucy G.; Jolly, Claire; Towers, Greg J.; Zuliani-Alvarez, Lorena; Bouhaddou, Mehdi; Obernier, Kirsten; Enjuanes Sánchez, Luis CSIC ORCID ; Fernández-Sousa, José M.; Plitidepsin – COVID - 19 Study Group; Krogan, Nevan J.; Jimeno, José M.; García-Sastre, Adolfo, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, McGovern, Briana L., Rodríguez, M. Luis, Enjuanes Sánchez, Luis, Fernández-Sousa, José M., Krogan, Nevan J., Jimeno, José M., García-Sastre, Adolfo, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), National Institute of Allergy and Infectious Diseases (US), Swiss National Science Foundation, Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Vergara-Alert, Júlia, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, Belgrano, Álvaro, Sopesén, Belén, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin; Thorne, Lucy G.; Jolly, Claire; Towers, Greg J.; Zuliani-Alvarez, Lorena; Bouhaddou, Mehdi; Obernier, Kirsten; Enjuanes Sánchez, Luis CSIC ORCID ; Fernández-Sousa, José M.; Plitidepsin – COVID - 19 Study Group; Krogan, Nevan J.; Jimeno, José M.; García-Sastre, Adolfo, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, McGovern, Briana L., Rodríguez, M. Luis, Enjuanes Sánchez, Luis, Fernández-Sousa, José M., Krogan, Nevan J., Jimeno, José M., and García-Sastre, Adolfo

Abstract

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.

Published
2022

26. SARS-CoV-2 evolution influences GBP and IFITM sensitivity

Author

Mesner, Dejan, primary, Reuschl, Ann-Kathrin, additional, Whelan, Matthew V. X., additional, Bronzovich, Taylor, additional, Haider, Tafhima, additional, Thorne, Lucy G., additional, Ragazzini, Roberta, additional, Bonfanti, Paola, additional, Towers, Greg J., additional, and Jolly, Clare, additional

Published
2023
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27. SARS-CoV-2 Variants Evolve Convergent Strategies to Remodel the Host Response

Author

Bouhaddou, Mehdi, primary, Reuschl, Ann-Kathrin, additional, Polacco, Benjamin J., additional, Thorne, Lucy G., additional, Ummadi, Manisha R., additional, Ye, Chengjin, additional, Rosales, Romel, additional, Pelin, Adrian, additional, Batra, Jyoti, additional, Jang, Gwendolyn, additional, Xu, Jiewei, additional, Moen, Jack M., additional, Richards, Alicia L., additional, Zhou, Yuan, additional, Harjai, Bhavya, additional, Stevenson, Erica, additional, Rojc, Ajda, additional, Ragazzini, Roberta, additional, Whelan, Matthew V.X., additional, Furnon, Wilhelm, additional, De Lorenzo, Giuditta, additional, Cowton, Vanessa, additional, Syed, Abdullah M., additional, Ciling, Alison, additional, Deutsch, Noa, additional, Pirak, Daniel, additional, Dowgier, Giulia, additional, Mesner, Dejan, additional, Turner, Jane L., additional, McGovern, Briana L., additional, Rodriguez, M. Luis, additional, Leiva-Rebollo, Rocio, additional, Dunham, Alistair S., additional, Zhong, Xiaofang, additional, Eckhardt, Manon, additional, Fossati, Andrea, additional, Liotta, Nicholas, additional, Kehrer, Thomas, additional, Cupic, Anastasija, additional, Rutkowska, Magda, additional, Mena, Nacho, additional, Aslam, Sadaf, additional, Hoffert, Alyssa, additional, Foussard, Helene, additional, Olwal, Charles, additional, Huang, Weiqing, additional, Zwaka, Thomas, additional, Pham, John, additional, Lyons, Molly, additional, Donahue, Laura, additional, Griffin, Aliesha, additional, Nugent, Rebecca, additional, Holden, Kevin, additional, Deans, Robert, additional, Aviles, Pablo, additional, López, José Antonio, additional, Jimeno Doñaque, José María, additional, Obernier, Kirsten, additional, Fabius, Jacqueline M., additional, Soucheray, Margaret, additional, Hüttenhain, Ruth, additional, Jungreis, Irwin, additional, Kellis, Manolis, additional, Echeverria, Ignacia, additional, Verba, Kliment, additional, Bonfanti, Paola, additional, Beltrao, Pedro, additional, Sharan, Roded, additional, Doudna, Jennifer A., additional, Martinez-Sobrido, Luis, additional, Patel, Arvind, additional, Palmarini, Massimo, additional, Miorin, Lisa, additional, White, Kris, additional, Swaney, Danielle L., additional, Garcia-Sastre, Adolfo, additional, Jolly, Clare, additional, Zuliani-Alvarez, Lorena, additional, Towers, Greg J., additional, and Krogan, Nevan J., additional

Published
2023
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28. SARS-CoV-2 variant biology: immune escape, transmission and fitness

Author

Carabelli, Alessandro M, Peacock, Thomas P, Thorne, Lucy G, Harvey, William T, Hughes, Joseph, COVID-19 Genomics UK Consortium, Peacock, Sharon J, Barclay, Wendy S, De Silva, Thushan I, Towers, Greg J, Robertson, David L, Carabelli, Alessandro M [0000-0003-3625-4021], Harvey, William T [0000-0001-9529-1127], Hughes, Joseph [0000-0003-2556-2563], Peacock, Sharon J [0000-0002-1718-2782], Robertson, David L [0000-0001-6338-0221], and Apollo - University of Cambridge Repository

Subjects
SARS-CoV-2, Humans, COVID-19, Biology, Immunity, Innate
Abstract

In late 2020, after circulating for almost a year in the human population, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited a major step change in its adaptation to humans. These highly mutated forms of SARS-CoV-2 had enhanced rates of transmission relative to previous variants and were termed 'variants of concern' (VOCs). Designated Alpha, Beta, Gamma, Delta and Omicron, the VOCs emerged independently from one another, and in turn each rapidly became dominant, regionally or globally, outcompeting previous variants. The success of each VOC relative to the previously dominant variant was enabled by altered intrinsic functional properties of the virus and, to various degrees, changes to virus antigenicity conferring the ability to evade a primed immune response. The increased virus fitness associated with VOCs is the result of a complex interplay of virus biology in the context of changing human immunity due to both vaccination and prior infection. In this Review, we summarize the literature on the relative transmissibility and antigenicity of SARS-CoV-2 variants, the role of mutations at the furin spike cleavage site and of non-spike proteins, the potential importance of recombination to virus success, and SARS-CoV-2 evolution in the context of T cells, innate immunity and population immunity. SARS-CoV-2 shows a complicated relationship among virus antigenicity, transmission and virulence, which has unpredictable implications for the future trajectory and disease burden of COVID-19.

Published
2023
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31. Author response: Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure

Author

Faysal, KM Rifat, primary, Walsh, James C, primary, Renner, Nadine, primary, Márquez, Chantal L, primary, Shah, Vaibhav B, additional, Tuckwell, Andrew J, additional, Christie, Michelle P, additional, Parker, Michael W, additional, Turville, Stuart G, additional, Towers, Greg J, additional, James, Leo C, additional, Jacques, David A, additional, and Böcking, Till, additional

Published
2022
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32. Global landscape of the host response to SARS-CoV-2 variants reveals viral evolutionary trajectories

Author

Bouhaddou, Mehdi, primary, Reuschl, Ann-Kathrin, additional, Polacco, Benjamin J., additional, Thorne, Lucy G., additional, Ummadi, Manisha R., additional, Ye, Chengjin, additional, Rosales, Romel, additional, Pelin, Adrian, additional, Batra, Jyoti, additional, Jang, Gwendolyn M., additional, Xu, Jiewei, additional, Moen, Jack M., additional, Richards, Alicia, additional, Zhou, Yuan, additional, Harjai, Bhavya, additional, Stevenson, Erica, additional, Rojc, Ajda, additional, Ragazzini, Roberta, additional, Whelan, Matthew V.X., additional, Furnon, Wilhelm, additional, De Lorenzo, Giuditta, additional, Cowton, Vanessa, additional, Syed, Abdullah M., additional, Ciling, Alison, additional, Deutsch, Noa, additional, Pirak, Daniel, additional, Dowgier, Giulia, additional, Mesner, Dejan, additional, Turner, Jane L., additional, McGovern, Briana L., additional, Rodriguez, M. Luis, additional, Leiva-Rebollo, Rocio, additional, Dunham, Alistair S., additional, Zhong, Xiaofang, additional, Eckhardt, Manon, additional, Fossati, Andrea, additional, Liotta, Nicholas, additional, Kehrer, Thomas, additional, Cupic, Anastasija, additional, Rutkowska, Magda, additional, Mena, Nacho, additional, Aslam, Sadaf, additional, Hoffert, Alyssa, additional, Foussard, Helene, additional, Pham, John, additional, Lyons, Molly, additional, Donahue, Laura, additional, Griffin, Aliesha, additional, Nugent, Rebecca, additional, Holden, Kevin, additional, Deans, Robert, additional, Aviles, Pablo, additional, López-Martín, José Antonio, additional, Jimeno, Jose M., additional, Obernier, Kirsten, additional, Fabius, Jacqueline M., additional, Soucheray, Margaret, additional, Hüttenhain, Ruth, additional, Jungreis, Irwin, additional, Kellis, Manolis, additional, Echeverria, Ignacia, additional, Verba, Kliment, additional, Bonfanti, Paola, additional, Beltrao, Pedro, additional, Sharan, Roded, additional, Doudna, Jennifer A., additional, Martinez-Sobrido, Luis, additional, Patel, Arvind, additional, Palmarini, Massimo, additional, Miorin, Lisa, additional, White, Kris, additional, Swaney, Danielle L., additional, García-Sastre, Adolfo, additional, Jolly, Clare, additional, Zuliani-Alvarez, Lorena, additional, Towers, Greg J., additional, and Krogan, Nevan J., additional

Published
2022
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33. Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure

Author

Faysal, K.M. Rifat, primary, Renner, Nadine, additional, Marquez, Chantal L, additional, Shah, Vaibhav, additional, Tuckwell, Andrew J, additional, Christie, Michelle P, additional, Parker, Michael W, additional, Turville, Stuart Grant, additional, James, Leo, additional, Towers, Greg J, additional, Jacques, David A, additional, and Boecking, Till, additional

Published
2022
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35. Evolution of enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants

Author

Reuschl, Ann-Kathrin, primary, Thorne, Lucy G., additional, Whelan, Matthew V.X., additional, Ragazzini, Roberta, additional, Furnon, Wilhelm, additional, Cowton, Vanessa M., additional, de Lorenzo, Giuditta, additional, Mesner, Dejan, additional, Turner, Jane L. E., additional, Dowgier, Giulia, additional, Bogoda, Nathasha, additional, Bonfanti, Paola, additional, Palmarini, Massimo, additional, Patel, Arvind H., additional, Jolly, Clare, additional, and Towers, Greg. J., additional

Published
2022
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38. Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19

Author

Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Vergara-Alert, Júlia, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, Belgrano, Álvaro, Sopesén, Belén, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, Enjuanes Sánchez, Luis CSIC ORCID, Fernández-Sousa, José M., Plitidepsin – COVID - 19 Study Group, Krogan, Nevan J., Jimeno, José M., García-Sastre, Adolfo, McGovern, Briana L., Rodríguez, M. Luis, Enjuanes Sánchez, Luis, Producció Animal, Sanitat Animal, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), National Institute of Allergy and Infectious Diseases (US), and Swiss National Science Foundation

Subjects
Adult, Male, Neutropenia, Health, Toxicology and Mutagenesis, Clinical Trials and Supportive Activities, Plant Science, Kaplan-Meier Estimate, Biochemistry, Genetics and Molecular Biology (miscellaneous), Cell Line, Clinical Research, Depsipeptides, Humans, Lung, Aged, Cancer, Cyclic, Tumor, Ecology, SARS-CoV-2, Prevention, COVID-19, Evaluation of treatments and therapeutic interventions, Length of Stay, Viral Load, Middle Aged, Preclinical, COVID-19 Drug Treatment, Hospitalization, Treatment Outcome, Infectious Diseases, Good Health and Well Being, 6.1 Pharmaceuticals, Drug Evaluation, Female, Patient Safety, Peptides
Abstract

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19., This work was supported by grants from the Government of Spain (PIE_INTRAMURAL_ LINEA 1 - 202020E079; PIE_INTRAMURAL_CSIC-202020E043). The research of CBIG consortium (constituted by IRTA-CReSA, BSC, & IrsiCaixa) is supported by Grifols pharmaceutical. We also acknowledge the crowdfunding initiative #Yomecorono (https://www.yomecorono.com). N Izquierdo-Useros has nonrestrictive funding from PharmaMar to study the antiviral effect of Plitidepsin. NJ Krogan was funded by grants from the National Institutes of Health (P50AI150476, U19AI135990, U19AI135972, R01AI143292, R01AI120694, and P01AI063302); by the Excellence in Research Award (ERA) from the Laboratory for Genomics Research (LGR), a collaboration between the University of California, San Francisco (UCSF), University of California, Berkley (UCB), and GlaxoSmithKline (GSK) (#133122P); by the Roddenberry Foundation, and gifts from QCRG philanthropic donors. This work was supported by the Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement #HR0011-19-2-0020. The views, opinions, and/or findings contained in this material are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. This research was partly funded by Center for Research for Influenza Pathogenesis and Transmission (CRIPT), a National Institute of Allergy and Infectious Diseases (NIAID) supported Center of Excellence for Influenza Research and Response (CEIRS, contract # 75N93021C00014), by DARPA grant HR0011-19-2-0020, by supplements to NIAID grants U19AI142733, U19AI135972, and DoD grant W81XWH-20-1-0270, and by the generous support of the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 (5384)), and anonymous donors to A García-Sastre. S Yildiz received funding from a Swiss National Foundation Early Postdoc Mobility fellowship (P2GEP3_184202).

Published
2022

43. Macrophage activation of cGAS and TRIM5 distinguish pandemic and non-pandemic HIV

Author

Zuliani-Alvarez, Lorena, primary, Larsen, Morten, additional, Rasaiyaah, Jane, additional, Monit, Chris, additional, Perry, Stephen O, additional, Sumner, Rebecca, additional, McAlpine-Scott, Simon, additional, Dickson, Claire, additional, Rifat Faysal, K. M., additional, Hilditch, Laura, additional, Miles, Richard, additional, Bibollet-Ruche, Frederic, additional, Hahn, Beatrice H, additional, Bocking, Till, additional, Pinotsis, Nicos, additional, James, Leo C, additional, Jacques, David, additional, and Towers, Greg J, additional

Published
2022
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44. Evolution of enhanced innate immune evasion by SARS-CoV-2

Author

Thorne, Lucy G., primary, Bouhaddou, Mehdi, additional, Reuschl, Ann-Kathrin, additional, Zuliani-Alvarez, Lorena, additional, Polacco, Ben, additional, Pelin, Adrian, additional, Batra, Jyoti, additional, Whelan, Matthew V. X., additional, Hosmillo, Myra, additional, Fossati, Andrea, additional, Ragazzini, Roberta, additional, Jungreis, Irwin, additional, Ummadi, Manisha, additional, Rojc, Ajda, additional, Turner, Jane, additional, Bischof, Marie L., additional, Obernier, Kirsten, additional, Braberg, Hannes, additional, Soucheray, Margaret, additional, Richards, Alicia, additional, Chen, Kuei-Ho, additional, Harjai, Bhavya, additional, Memon, Danish, additional, Hiatt, Joseph, additional, Rosales, Romel, additional, McGovern, Briana L., additional, Jahun, Aminu, additional, Fabius, Jacqueline M., additional, White, Kris, additional, Goodfellow, Ian G., additional, Takeuchi, Yasu, additional, Bonfanti, Paola, additional, Shokat, Kevan, additional, Jura, Natalia, additional, Verba, Klim, additional, Noursadeghi, Mahdad, additional, Beltrao, Pedro, additional, Kellis, Manolis, additional, Swaney, Danielle L., additional, García-Sastre, Adolfo, additional, Jolly, Clare, additional, Towers, Greg J., additional, and Krogan, Nevan J., additional

Published
2021
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45. Induction of transposable element expression is central to innate sensing

Author

Rookhuizen, Derek C, primary, Bonte, Pierre-Emmanuel, additional, Ye, Mengliang, additional, Hoyler, Thomas, additional, Gentili, Matteo, additional, Burgdorf, Nina, additional, Durand, Sylvere, additional, Apprahamian, Fanny, additional, Kroemer, Guido, additional, Manel, Nicolas, additional, Waterfall, Joshua, additional, Milne, Richard, additional, Goudot, Christel, additional, Towers, Greg J, additional, and Amigorena, Sebastian, additional

Published
2021
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46. HIV-1 evades innate immune recognition through specific cofactor recruitment

Author

Rasaiyaah, Jane, Tan, Choon Ping, Fletcher, Adam J., Price, Amanda J., Blondeau, Caroline, Hilditch, Laura, Jacques, David A., Selwood, David L., James, Leo C., Noursadeghi, Mahdad, and Towers, Greg J.

Subjects
Gene expression -- Research, Immune response -- Genetic aspects, HIV infection -- Development and progression -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Human immunodeficiency virus (HIV)-1 is able to replicate in primary human macrophages without stimulating innate immunity despite reverse transcription of genomic RNA into double-stranded DNA, an activity that might be expected to trigger innate pattern recognition receptors. We reasoned that if correctly orchestrated HIV-1 uncoating and nuclear entry is important for evasion of innate sensors then manipulation of specific interactions between HIV-1 capsid and host factors that putatively regulate these processes should trigger pattern recognition receptors and stimulate type 1 interferon (IFN) secretion. Here we show that HIV-1 capsid mutants N74D and P90A, which are impaired for interaction with cofactors cleavage and polyadenylation specificity factor subunit 6 (CPSF6) and cyclophilins (Nup358 and CypA), respectively (1,2), cannot replicate in primary human monocyte-derived macrophages because they trigger innate sensors leading to nuclear translocation of NF-κB and IRF3, the production of soluble type 1 IFN and induction of an antiviral state. Depletion of CPSF6 with short hairpin RNA expression allows wild-type virus to trigger innate sensors and IFN production. In each case, suppressed replication is rescued by IFN-receptor blockade, demonstrating a role for IFN in restriction. IFN production is dependent on viral reverse transcription but not integration, indicating that a viral reverse transcription product comprises the HIV-1 pathogen-associated molecular pattern. Finally, we show that we can pharmacologically induce wild-type HIV-1 infection to stimulate IFN secretion and an antiviral state using a non-immunosuppressive cyclosporine analogue. We conclude that HIV-1 has evolved to use CPSF6 and cyclophilins to cloak its replication, allowing evasion of innate immune sensors and induction of a cell-autonomous innate immune response in primary human macrophages., HIV-1 capsid (CA) mutant N74D cannot recruit CPSF6 and is insensitive to depletion of HIV-1 cofactors Nup358 and TNPO3, suggesting that it may use alternate cofactors for nuclear entry (1-3). [...]

Published
2013

49. Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant

Author

Thorne, Lucy G, primary, Bouhaddou, Mehdi, additional, Reuschl, Ann-Kathrin, additional, Zuliani-Alvarez, Lorena, additional, Polacco, Ben, additional, Pelin, Adrian, additional, Batra, Jyoti, additional, Whelan, Matthew V.X., additional, Ummadi, Manisha, additional, Rojc, Ajda, additional, Turner, Jane, additional, Obernier, Kirsten, additional, Braberg, Hannes, additional, Soucheray, Margaret, additional, Richards, Alicia, additional, Chen, Kuei-Ho, additional, Harjai, Bhavya, additional, Memon, Danish, additional, Hosmillo, Myra, additional, Hiatt, Joseph, additional, Jahun, Aminu, additional, Goodfellow, Ian G., additional, Fabius, Jacqueline M., additional, Shokat, Kevan, additional, Jura, Natalia, additional, Verba, Klim, additional, Noursadeghi, Mahdad, additional, Beltrao, Pedro, additional, Swaney, Danielle L., additional, Garcia-Sastre, Adolfo, additional, Jolly, Clare, additional, Towers, Greg J., additional, and Krogan, Nevan J., additional

Published
2021
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50. Plitidepsin has a positive therapeutic index in adult patients with COVID-19 requiring hospitalization

Author

PharmaMar, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), Centers of Excellence for Influenza Research and Surveillance (US), JPB Foundation, Swiss National Science Foundation, López-Martín, José A. [0000-0001-7530-3207], Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Sopesén, Belén, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, Enjuanes Sánchez, Luis, Fernández-Sousa, José M., Plitidepsin – COVID - 19 Study Group, Krogan, Nevan J., Jimeno, José M., García-Sastre, Adolfo, PharmaMar, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), Centers of Excellence for Influenza Research and Surveillance (US), JPB Foundation, Swiss National Science Foundation, López-Martín, José A. [0000-0001-7530-3207], Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Sopesén, Belén, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, Enjuanes Sánchez, Luis, Fernández-Sousa, José M., Plitidepsin – COVID - 19 Study Group, Krogan, Nevan J., Jimeno, José M., and García-Sastre, Adolfo

Abstract

Plitidepsin is a marine-derived cyclic-peptide that inhibits SARS-CoV-2 replication at low nanomolar concentrations by the targeting of host protein eEF1A (eukaryotic translation-elongation-factor-1A). We evaluated a model of intervention with plitidepsin in hospitalized COVID-19 adult patients where three doses were assessed (1.5, 2 and 2.5 mg/day for 3 days, as a 90-minute intravenous infusion) in 45 patients (15 per dose-cohort). Treatment was well tolerated, with only two Grade 3 treatment-related adverse events observed (hypersensitivity and diarrhea). The discharge rates by Days 8 and 15 were 56.8% and 81.8%, respectively, with data sustaining dose-effect. A mean 4.2 log10 viral load reduction was attained by Day 15. Improvement in inflammation markers was also noted in a seemingly dose-dependent manner. These results suggest that plitidepsin impacts the outcome of patients with COVID-19.

Published
2021

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