47 results on '"Mesalam, Ahmed Atef"'
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2. Attenuation of Oxidative Stress and Regulation of AKT Signaling by Vanillic Acid during Bovine Pre-Implantation Embryo Development
- Author
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El-Sheikh, Marwa, primary, Mesalam, Ayman, additional, Joo, Myeong-Don, additional, Sidrat, Tabinda, additional, Mesalam, Ahmed Atef, additional, and Kong, Il-Keun, additional
- Published
- 2023
- Full Text
- View/download PDF
3. First Report on Abnormal Renal Function in Acute Hepatitis E Genotype 1 Infection
- Author
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Elkhawaga, Amal A., primary, El-Mokhtar, Mohamed A., additional, Mahmoud, Amal A., additional, Ali, Wael Esmat, additional, Mohamed, Doaa Safwat, additional, Kamel, Ayat M., additional, Mesalam, Ahmed Atef, additional, Mousa, Nermien H. S., additional, Ashmawy, Ahmed M., additional, Abdel Aziz, Essam M., additional, Sayed, Ibrahim M., additional, Ramadan, Haidi Karam-Allah, additional, and Elkholy, Yasmine Samy, additional
- Published
- 2023
- Full Text
- View/download PDF
4. Modulation of Apoptosis and Autophagy by Melatonin in Juglone-Exposed Bovine Oocytes
- Author
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El-Sheikh, Marwa, primary, Mesalam, Ahmed Atef, additional, Kang, Seon-Min, additional, Joo, Myeong-Don, additional, Soliman, Seham Samir, additional, Khalil, Atif Ali Khan, additional, Ahn, Mi-Jeong, additional, and Kong, Il-Keun, additional
- Published
- 2023
- Full Text
- View/download PDF
5. Downregulation of PI3K/AKT/mTOR Pathway in Juglone-Treated Bovine Oocytes
- Author
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El-Sheikh, Marwa, primary, Mesalam, Ayman, additional, Khalil, Atif Ali Khan, additional, Idrees, Muhammad, additional, Ahn, Mi-Jeong, additional, Mesalam, Ahmed Atef, additional, and Kong, Il-Keun, additional
- Published
- 2023
- Full Text
- View/download PDF
6. The First Report of Coxiella burnetii as a Potential Neglected Pathogen of Acute Hepatitis of Unknown Causes in Egypt
- Author
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El-Mokhtar, Mohamed A., primary, Sayed, Ibrahim M., additional, Kamel, Ayat M., additional, Mesalam, Ahmed Atef, additional, Elgohary, Elsayed A., additional, Khalaf, Khaled Abo bakr, additional, Adel, Sara, additional, Elfadl, Azza Abo, additional, Khalifa, Walaa A., additional, and Ramadan, Haidi Karam-Allah, additional
- Published
- 2022
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- View/download PDF
7. A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo
- Author
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Desombere, Isabelle, Mesalam, Ahmed Atef, Urbanowicz, Richard A., Van Houtte, Freya, Verhoye, Lieven, Keck, Zhen-Yong, Farhoudi, Ali, Vercauteren, Koen, Weening, Karin E., Baumert, Thomas F., Patel, Arvind H., Foung, Steven K.H., Ball, Jonathan, Leroux-Roels, Geert, and Meuleman, Philip
- Published
- 2017
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8. Antimicrobial Resistance of Salmonella enteritidis and Salmonella typhimurium Isolated from Laying Hens, Table Eggs, and Humans with Respect to Antimicrobial Activity of Biosynthesized Silver Nanoparticles
- Author
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Abou Elez, Rasha M. M., primary, Elsohaby, Ibrahim, additional, El-Gazzar, Nashwa, additional, Tolba, Hala M. N., additional, Abdelfatah, Eman N., additional, Abdellatif, Samah S., additional, Mesalam, Ahmed Atef, additional, and Tahoun, Asmaa B. M. B., additional
- Published
- 2021
- Full Text
- View/download PDF
9. Successful anti-scavenger receptor class B type I (SR-BI) monoclonal antibody therapy in humanized mice after challenge with HCV variants with in vitro resistance to SR-BI-targeting agents
- Author
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Vercauteren, Koen, Van Den Eede, Naomi, Mesalam, Ahmed Atef, Belouzard, Sandrine, Catanese, Maria Teresa, Bankwitz, Dorothea, Wong-Staal, Flossie, Cortese, Riccardo, Dubuisson, Jean, Rice, Charles M., Pietschmann, Thomas, Leroux-Roels, Geert, Nicosia, Alfredo, and Meuleman, Philip
- Published
- 2014
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- View/download PDF
10. Characterization of NS3 protease from an Egyptian HCV genotype 4a isolate
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Bahgat, Mahmoud Mohamed, Ibrahim, Ahmed Atef, Abd-Elshafy, Dina Nadeem, Mesalam, Ahmed Atef, Gewaid, Hossam Eid, Ismaeil, Amany Abd-Elghany, El-Waseef, Ahmed Mohamed, Maghraby, Amany Sayed, Barakat, Ahmed Barakat, El-Far, Mohamed Abd-Elhafez, Ghanem, Hossam El-Din Ahmed, Mohamed, Amro Mahmoud, and Ali, Mohamed Ahmed
- Published
- 2009
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11. Melatonin Alleviates the Toxicity of High Nicotinamide Concentrations in Oocytes: Potential Interaction with Nicotinamide Methylation Signaling
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El-Sheikh, Marwa, primary, Mesalam, Ahmed Atef, additional, Song, Seok-Hwan, additional, Ko, Jonghyeok, additional, and Kong, Il-Keun, additional
- Published
- 2021
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- View/download PDF
12. Induction of Oxidative Stress and Mitochondrial Dysfunction by Juglone Affects the Development of Bovine Oocytes
- Author
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Mesalam, Ahmed Atef, primary, El-Sheikh, Marwa, additional, Joo, Myeong-Don, additional, Khalil, Atif Ali Khan, additional, Mesalam, Ayman, additional, Ahn, Mi-Jeong, additional, and Kong, Il-Keun, additional
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- 2020
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13. Hepatitis C Virus Vaccine Development: A Step Forward
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Mesalam, Ahmed Atef, primary
- Published
- 2020
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14. Nicotinamide Supplementation during the In Vitro Maturation of Oocytes Improves the Developmental Competence of Preimplantation Embryos: Potential Link to SIRT1/AKT Signaling
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El Sheikh, Marwa, primary, Mesalam, Ahmed Atef, additional, Idrees, Muhammad, additional, Sidrat, Tabinda, additional, Mesalam, Ayman, additional, Lee, Kyeong-Lim, additional, and Kong, Il-Keun, additional
- Published
- 2020
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- View/download PDF
15. Development and characterization of a human monoclonal antibody targeting the N-terminal region of hepatitis C virus envelope glycoprotein E1
- Author
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Mesalam, Ahmed Atef, Desombere, Isabelle, Farhoudi, Ali, Van Houtte, Freya, Verhoye, Lieven, Ball, Jonathan, Dubuisson, Jean, Foung, Steven K.H., Patel, Arvind H., Persson, Mats A.A., Leroux-Roels, Geert, and Meuleman, Philip
- Subjects
Hepatitis C virus ,EntryVaccine ,Envelope protein ,Antibody - Abstract
Monoclonal antibodies (mAbs) targeting the hepatitis C virus (HCV) envelope have been raised mainly against envelope protein 2 (E2), while the antigenic epitopes of envelope protein 1 (E1) are not fully identified. Here we describe the detailed characterization of a human mAb, designated A6, generated from an HCV genotype 1b infected patient. ELISA results showed reactivity of mAb A6 to full-length HCV E1E2 of genotypes 1a, 1b and 2a. Epitope mapping identified a region spanning amino acids 230–239 within the N-terminal region of E1 as critical for binding. Antibody binding to this epitope was not conformation dependent. Neutralization assays showed that mAb A6 lacks neutralizing capacity and does not interfere with the activity of known neutralizing antibodies. In summary, mAb A6 is an important tool to study the structure and function of E1 within the viral envelope, a crucial step in the development of an effective prophylactic HCV vaccine.
- Published
- 2018
16. Melatonin Abrogates the Anti-Developmental Effect of the AKT Inhibitor SH6 in Bovine Oocytes and Embryos
- Author
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El Sheikh, Marwa, primary, Mesalam, Ayman, additional, Mesalam, Ahmed Atef, additional, Idrees, Muhammad, additional, Lee, Kyeong-Lim, additional, and Kong, Il-Keun, additional
- Published
- 2019
- Full Text
- View/download PDF
17. Development and characterization of a human monoclonal antibody for prevention of HCV recurrence in liver transplant patients
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Mesalam, Ahmed Atef Ahmed Abouzeid, Desombere, Isabelle, Urbanowicz, Richard, Johansson, Daniel X, Vercauteren, Koen, Farhoudi Moghadam, Aliasghar, Van Houtte, Freya, Verhoye, Lieven, Persson, Mats, Ball, Jonathan, Leroux-Roels, Geert, and Meuleman, Philip
- Subjects
Medicine and Health Sciences - Abstract
More than 170 million people worldwide are chronically infected with hepatitis C virus (HCV) and are at risk of developing liver fibrosis, cirrhosis and hepatocellular carcinoma. Liver transplantation is the only option for patients with HCV-induced end-stage liver diseases. Nevertheless, infection of the newly grafted liver occurs immediately and universally after transplantation. Despite the recent progress in HCV therapy, a prophylactic vaccine is still not available. The role of neutralizing monoclonal antibodies (mAbs) in protection from different viral infections including HCV, HIV and Ebola has been reported. In the last few years, several mAbs with neutralizing activity have been described but only few mAbs have been evaluated in vivo. In the present study, we describe the development of a mAb, designated 2A5, isolated from HCV genotype 1b chronic patient. ELISA results indicated high affinity of mAb 2A5 towards HCV envelope glycoprotein (E1E2). The binding activity was completely lost against denatured E1E2 protein indicating that it targets a conformational epitope within the envelope region. Epitope mapping using alanine mutants of E1E2 proteins defined critical binding residues within the regions 419-447 and 612-617. Results of pseudoparticles (HCVpp) and cell culture produced virus (HCVcc) neutralization showed broad neutralizing activity of mAb 2A5 against all HCV genotypes. The efficacy study of mAb 2A5 in immune-deficient mice of which the liver is repopulated with human hepatocytes (humanized mice) showed complete protection from HCV challenge for genotypes 1a and 4a, while partial protection was achieved for genotypes 1b and 6a. Sequence analysis of E1E2 protein from non-protected mice did not revealed resistance mutations at interaction residues of mAb 2A5. In conclusion, mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence provide an effective strategy to prevent HCV recurrence in chronically infected HCV liver transplant patients. In addition, the broad neutralizing activity of this mAb presents a valuable epitope for the design of HCV vaccine with cross-protection activity.
- Published
- 2017
18. Functional Study of the C-Terminal Part of the Hepatitis C Virus E1 Ectodomain
- Author
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Moustafa, Rehab I., primary, Haddad, Juliano G., additional, Linna, Lydia, additional, Hanoulle, Xavier, additional, Descamps, Véronique, additional, Mesalam, Ahmed Atef, additional, Baumert, Thomas F., additional, Duverlie, Gilles, additional, Meuleman, Philip, additional, Dubuisson, Jean, additional, and Lavie, Muriel, additional
- Published
- 2018
- Full Text
- View/download PDF
19. Animal Models to Study Hepatitis C Virus Infection
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Burm, Rani, primary, Collignon, Laura, additional, Mesalam, Ahmed Atef, additional, and Meuleman, Philip, additional
- Published
- 2018
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20. A broadly neutralizing monoclonal antibody targeting HCV prevents viral infection in vitro and in human liver chimeric mice
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Mesalam, Ahmed Atef Ahmed Abouzeid
- Subjects
Medicine and Health Sciences - Published
- 2016
21. Hepatitis C Virus Vaccine Development: A Step Forward.
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Mesalam, Ahmed Atef
- Subjects
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HEPATITIS C vaccines , *VACCINE development , *HEPATITIS C , *RESPIRATORY infections , *IMMUNE serums , *FERRITIN , *RECOMBINANT proteins , *VACCINES , *VIRAL hepatitis , *HEPATITIS viruses , *VIRAL antibodies - Published
- 2021
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22. Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus
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Vausselin, Thibaut, primary, Séron, Karin, additional, Lavie, Muriel, additional, Mesalam, Ahmed Atef, additional, Lemasson, Matthieu, additional, Belouzard, Sandrine, additional, Fénéant, Lucie, additional, Danneels, Adeline, additional, Rouillé, Yves, additional, Cocquerel, Laurence, additional, Foquet, Lander, additional, Rosenberg, Arielle R., additional, Wychowski, Czeslaw, additional, Meuleman, Philip, additional, Melnyk, Patricia, additional, and Dubuisson, Jean, additional
- Published
- 2016
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- View/download PDF
23. Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action
- Author
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Calland, Noémie, primary, Sahuc, Marie-Emmanuelle, additional, Belouzard, Sandrine, additional, Pène, Véronique, additional, Bonnafous, Pierre, additional, Mesalam, Ahmed Atef, additional, Deloison, Gaspard, additional, Descamps, Véronique, additional, Sahpaz, Sevser, additional, Wychowski, Czeslaw, additional, Lambert, Olivier, additional, Brodin, Priscille, additional, Duverlie, Gilles, additional, Meuleman, Philip, additional, Rosenberg, Arielle R., additional, Dubuisson, Jean, additional, Rouillé, Yves, additional, and Séron, Karin, additional
- Published
- 2015
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24. Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice
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Vercauteren, Koen, primary, Brown, Richard J P, additional, Mesalam, Ahmed Atef, additional, Doerrbecker, Juliane, additional, Bhuju, Sabin, additional, Geffers, Robert, additional, Van Den Eede, Naomi, additional, McClure, C Patrick, additional, Troise, Fulvia, additional, Verhoye, Lieven, additional, Baumert, Thomas, additional, Farhoudi, Ali, additional, Cortese, Riccardo, additional, Ball, Jonathan K, additional, Leroux-Roels, Geert, additional, Pietschmann, Thomas, additional, Nicosia, Alfredo, additional, and Meuleman, Philip, additional
- Published
- 2015
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- View/download PDF
25. Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice.
- Author
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Vercauteren, Koen, Brown, Richard J. P., Mesalam, Ahmed Atef, Doerrbecker, Juliane, Bhuju, Sabin, Geffers, Robert, Van Den Eede, Naomi, McClure, C. Patrick, Troise, Fulvia, Verhoye, Lieven, Baumert, Thomas, Farhoudi, Ali, Cortese, Riccardo, Ball, Jonathan K., Leroux-Roels, Geert, Pietschmann, Thomas, Nicosia, Alfredo, and Meuleman, Philip
- Subjects
HEPATITIS C treatment ,ANTIVIRAL agents ,DRUG resistance in microorganisms ,TARGETED drug delivery ,LIVER disease treatment ,LABORATORY mice - Published
- 2016
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26. Successful anti-scavenger receptor class B type I (SR-BI) monoclonal antibody therapy in humanized mice after challenge with HCV variants within vitroresistance to SR-BI-targeting agents
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Vercauteren, Koen, primary, Van Den Eede, Naomi, additional, Mesalam, Ahmed Atef, additional, Belouzard, Sandrine, additional, Catanese, Maria Teresa, additional, Bankwitz, Dorothea, additional, Wong-Staal, Flossie, additional, Cortese, Riccardo, additional, Dubuisson, Jean, additional, Rice, Charles M., additional, Pietschmann, Thomas, additional, Leroux-Roels, Geert, additional, Nicosia, Alfredo, additional, and Meuleman, Philip, additional
- Published
- 2014
- Full Text
- View/download PDF
27. Impact of lipids and lipoproteins on hepatitis C virus infection and virus neutralization
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Vercauteren, Koen, primary, Mesalam, Ahmed Atef, additional, Leroux-Roels, Geert, additional, and Meuleman, Philip, additional
- Published
- 2014
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- View/download PDF
28. Schistosoma mansoni soluble egg antigens enhance HCV replication in mammalian cells
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Bahgat, Mahmoud Mohamed, primary, El-Far, Mohamed Abd-Elhafez, additional, Mesalam, Ahmed Atef, additional, Ismaeil, Amany Abd-Elghany, additional, Ibrahim, Ahmed Atef, additional, Gewaid, Hossam Eid, additional, Maghraby, Amany Sayed, additional, Ali, Mohamed Ahmed, additional, and Abd-Elshafy, Dina Nadeem, additional
- Published
- 2010
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- View/download PDF
29. Induction of Oxidative Stress and Mitochondrial Dysfunction by Juglone Affects the Development of Bovine Oocytes.
- Author
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Mesalam, Ahmed Atef, El-Sheikh, Marwa, Joo, Myeong-Don, Khalil, Atif Ali Khan, Mesalam, Ayman, Ahn, Mi-Jeong, and Kong, Il-Keun
- Subjects
- *
OXIDATIVE stress , *MITOCHONDRIA , *BOS , *REACTIVE oxygen species , *WALNUT - Abstract
Juglone, a major naphthalenedione component of walnut trees, has long been used in traditional medicine as an antimicrobial and antitumor agent. Nonetheless, its impact on oocyte and preimplantation embryo development has not been entirely clarified. Using the bovine model, we sought to elucidate the impact of juglone treatment during the in vitro maturation (IVM) of oocytes on their maturation and development of embryos. Results showed a severe reduction in oocyte nuclear maturation and cumulus expansion and a significant increase in mitochondrial dysfunction and reactive oxygen species (ROS) levels in cumulus–oocyte complexes (COCs) treated with juglone (12.5, 25.0, and 50.0 µM). In addition, RT–qPCR showed downregulation of the expansion-related (HAS2, TNFAIP6, PTX3, and PTGS2) and mitochondrial (ATPase6 and ATP5F1E) genes in juglone-treated COCs. Moreover, the development rates of day 4 total cleavage and 8–16 cell stage embryos, as well as day 8 blastocysts, were significantly reduced following exposure to juglone. Using immunofluorescence, the apoptotic marker caspase-9 was overexpressed in oocytes exposed to juglone (25.0 µM) compared to the untreated control. In conclusion, our study reports that exposing bovine oocytes to 12.5–50.0 µM of juglone can reduce their development through the direct induction of ROS accumulation, apoptosis, and mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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30. A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo
- Author
-
Desombere, Isabelle, Mesalam, Ahmed Atef, Urbanowicz, Richard A., Van Houtte, Freya, Verhoye, Lieven, Keck, Zhen-Yong, Farhoudi, Ali, Vercauteren, Koen, Weening, Karin E., Baumert, Thomas F., Patel, Arvind H., Foung, Steven K.H., Ball, Jonathan, Leroux-Roels, Geert, Meuleman, Philip, Desombere, Isabelle, Mesalam, Ahmed Atef, Urbanowicz, Richard A., Van Houtte, Freya, Verhoye, Lieven, Keck, Zhen-Yong, Farhoudi, Ali, Vercauteren, Koen, Weening, Karin E., Baumert, Thomas F., Patel, Arvind H., Foung, Steven K.H., Ball, Jonathan, Leroux-Roels, Geert, and Meuleman, Philip
- Abstract
Infections with hepatitis C virus (HCV) represent a worldwide health burden and a prophylactic vaccine is still not available. Liver transplantation (LT) is often the only option for patients with HCV-induced end-stage liver disease. However, immediately after transplantation, the liver graft becomes infected by circulating virus, resulting in accelerated progression of liver disease. Although the effi cacy of HCV treatment using direct-acting antivirals has improved significantly, immune compromised LT-patients and patients with advanced liver disease remain difficult to treat. As an alternative approach, interfering with viral entry could prevent infection of the donor liver. We generated a human monoclonal antibody (mAb), designated 2A5, which targets the HCV envelope. The neutralizing activity of mAb 2A5 was assessed using multiple prototype and patient-derived HCV pseudoparticles (HCVpp), cell culture produced HCV (HCVcc), and a human-liver chimeric mouse model. Neutralization levels observed for mAb 2A5 were generally high and mostly superior to those obtained with AP33, a well-characterized HCV-neutralizing monoclonal antibody. Using humanized mice, complete protection was observed after genotype 1a and 4a HCV challenge, while only partial protection was achieved using gt1b and 6a isolates. Epitope mapping revealed that mAb 2A5 binding is conformation-dependent and identified the E2-region spanning amino acids 434 to 446 (epitope II) as the predominant contact domain. Conclusion : mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence represent a valuable candidate to prevent HCV recurrence in LT-patients. In addition, the detailed identification of the neutralizing epitope can be applied for the design of prophylactic HCV vaccines.
- Full Text
- View/download PDF
31. Development and characterization of a human monoclonal antibody targeting the N-terminal region of hepatitis C virus envelope glycoprotein E1
- Author
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Mesalam, Ahmed Atef, Desombere, Isabelle, Farhoudi, Ali, Van Houtte, Freya, Verhoye, Lieven, Ball, Jonathan, Dubuisson, Jean, Foung, Steven K.H., Patel, Arvind H., Persson, Mats A.A., Leroux-Roels, Geert, Meuleman, Philip, Mesalam, Ahmed Atef, Desombere, Isabelle, Farhoudi, Ali, Van Houtte, Freya, Verhoye, Lieven, Ball, Jonathan, Dubuisson, Jean, Foung, Steven K.H., Patel, Arvind H., Persson, Mats A.A., Leroux-Roels, Geert, and Meuleman, Philip
- Abstract
Monoclonal antibodies (mAbs) targeting the hepatitis C virus (HCV) envelope have been raised mainly against envelope protein 2 (E2), while the antigenic epitopes of envelope protein 1 (E1) are not fully identified. Here we describe the detailed characterization of a human mAb, designated A6, generated from an HCV genotype 1b infected patient. ELISA results showed reactivity of mAb A6 to full-length HCV E1E2 of genotypes 1a, 1b and 2a. Epitope mapping identified a region spanning amino acids 230-239 within the N-terminal region of E1 as critical for binding. Antibody binding to this epitope was not conformation dependent. Neutralization assays showed that mAb A6 lacks neutralizing capacity and does not interfere with the activity of known neutralizing antibodies. In summary, mAb A6 is an important tool to study the structure and function of E1 within the viral envelope, a crucial step in the development of an effective prophylactic HCV vaccine.
- Full Text
- View/download PDF
32. Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice
- Author
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Vercauteren, Koen, Brown, Richard J.P., Mesalam, Ahmed Atef, Doerrbecker, Juliane, Bhuju, Sabin, Geffers, Robert, Van Den Eede, Naomi, McClure, C. Patrick, Troise, Fulvia, Verhoye, Lieven, Baumert, Thomas, Farhoudi, Ali, Cortese, Riccardo, Ball, Jonathan K., Leroux-Roels, Geert, Pietschmann, Thomas, Nicosia, Alfredo, Meuleman, Philip, Vercauteren, Koen, Brown, Richard J.P., Mesalam, Ahmed Atef, Doerrbecker, Juliane, Bhuju, Sabin, Geffers, Robert, Van Den Eede, Naomi, McClure, C. Patrick, Troise, Fulvia, Verhoye, Lieven, Baumert, Thomas, Farhoudi, Ali, Cortese, Riccardo, Ball, Jonathan K., Leroux-Roels, Geert, Pietschmann, Thomas, Nicosia, Alfredo, and Meuleman, Philip
- Abstract
Objective: Direct-acting antivirals (DAAs) inhibit hepatitis C virus (HCV) infection by targeting viral proteins that play essential roles in the replication process. However, selection of resistance-associated variants (RAVs) during DAA therapy has been a cause of therapeutic failure. In this study, we wished to address whether such RAVs could be controlled by the co-administration of host-targeting entry inhibitors that prevent intrahepatic viral spread. Design: We investigated the effect of adding an entry inhibitor (the anti-scavenger receptor class B type I mAb1671) to a DAA monotherapy (the protease inhibitor ciluprevir) in human-liver mice chronically infected with HCV of genotype 1b. Clinically relevant non-laboratory strains were used to achieve viraemia consisting of a cloud of related viral variants (quasispecies) and the emergence of RAVs was monitored at high resolution using next-generation sequencing. Results: HCV-infected human-liver mice receiving DAA monotherapy rapidly experienced on-therapy viral breakthrough. Deep sequencing of the HCV protease domain confirmed the manifestation of drug-resistant mutants upon viral rebound. In contrast, none of the mice treated with a combination of the DAA and the entry inhibitor experienced on-therapy viral breakthrough, despite detection of RAV emergence in some animals. Conclusions: This study provides preclinical in vivo evidence that addition of an entry inhibitor to an anti-HCV DAA regimen restricts the breakthrough of DAA-resistant viruses. Our approach is an excellent strategy to prevent therapeutic failure caused by on-therapy rebound of DAA-RAVs. Inclusion of an entry inhibitor to the newest DAA combination therapies may further increase response rates, especially in difficult-to-treat patient populations.
- Full Text
- View/download PDF
33. Development and characterization of a human monoclonal antibody targeting the N-terminal region of hepatitis C virus envelope glycoprotein E1
- Author
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Mesalam, Ahmed Atef, Desombere, Isabelle, Farhoudi, Ali, Van Houtte, Freya, Verhoye, Lieven, Ball, Jonathan, Dubuisson, Jean, Foung, Steven K.H., Patel, Arvind H., Persson, Mats A.A., Leroux-Roels, Geert, Meuleman, Philip, Mesalam, Ahmed Atef, Desombere, Isabelle, Farhoudi, Ali, Van Houtte, Freya, Verhoye, Lieven, Ball, Jonathan, Dubuisson, Jean, Foung, Steven K.H., Patel, Arvind H., Persson, Mats A.A., Leroux-Roels, Geert, and Meuleman, Philip
- Abstract
Monoclonal antibodies (mAbs) targeting the hepatitis C virus (HCV) envelope have been raised mainly against envelope protein 2 (E2), while the antigenic epitopes of envelope protein 1 (E1) are not fully identified. Here we describe the detailed characterization of a human mAb, designated A6, generated from an HCV genotype 1b infected patient. ELISA results showed reactivity of mAb A6 to full-length HCV E1E2 of genotypes 1a, 1b and 2a. Epitope mapping identified a region spanning amino acids 230-239 within the N-terminal region of E1 as critical for binding. Antibody binding to this epitope was not conformation dependent. Neutralization assays showed that mAb A6 lacks neutralizing capacity and does not interfere with the activity of known neutralizing antibodies. In summary, mAb A6 is an important tool to study the structure and function of E1 within the viral envelope, a crucial step in the development of an effective prophylactic HCV vaccine.
- Full Text
- View/download PDF
34. A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo
- Author
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Desombere, Isabelle, Mesalam, Ahmed Atef, Urbanowicz, Richard A., Van Houtte, Freya, Verhoye, Lieven, Keck, Zhen-Yong, Farhoudi, Ali, Vercauteren, Koen, Weening, Karin E., Baumert, Thomas F., Patel, Arvind H., Foung, Steven K.H., Ball, Jonathan, Leroux-Roels, Geert, Meuleman, Philip, Desombere, Isabelle, Mesalam, Ahmed Atef, Urbanowicz, Richard A., Van Houtte, Freya, Verhoye, Lieven, Keck, Zhen-Yong, Farhoudi, Ali, Vercauteren, Koen, Weening, Karin E., Baumert, Thomas F., Patel, Arvind H., Foung, Steven K.H., Ball, Jonathan, Leroux-Roels, Geert, and Meuleman, Philip
- Abstract
Infections with hepatitis C virus (HCV) represent a worldwide health burden and a prophylactic vaccine is still not available. Liver transplantation (LT) is often the only option for patients with HCV-induced end-stage liver disease. However, immediately after transplantation, the liver graft becomes infected by circulating virus, resulting in accelerated progression of liver disease. Although the effi cacy of HCV treatment using direct-acting antivirals has improved significantly, immune compromised LT-patients and patients with advanced liver disease remain difficult to treat. As an alternative approach, interfering with viral entry could prevent infection of the donor liver. We generated a human monoclonal antibody (mAb), designated 2A5, which targets the HCV envelope. The neutralizing activity of mAb 2A5 was assessed using multiple prototype and patient-derived HCV pseudoparticles (HCVpp), cell culture produced HCV (HCVcc), and a human-liver chimeric mouse model. Neutralization levels observed for mAb 2A5 were generally high and mostly superior to those obtained with AP33, a well-characterized HCV-neutralizing monoclonal antibody. Using humanized mice, complete protection was observed after genotype 1a and 4a HCV challenge, while only partial protection was achieved using gt1b and 6a isolates. Epitope mapping revealed that mAb 2A5 binding is conformation-dependent and identified the E2-region spanning amino acids 434 to 446 (epitope II) as the predominant contact domain. Conclusion : mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence represent a valuable candidate to prevent HCV recurrence in LT-patients. In addition, the detailed identification of the neutralizing epitope can be applied for the design of prophylactic HCV vaccines.
- Full Text
- View/download PDF
35. Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice
- Author
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Vercauteren, Koen, Brown, Richard J.P., Mesalam, Ahmed Atef, Doerrbecker, Juliane, Bhuju, Sabin, Geffers, Robert, Van Den Eede, Naomi, McClure, C. Patrick, Troise, Fulvia, Verhoye, Lieven, Baumert, Thomas, Farhoudi, Ali, Cortese, Riccardo, Ball, Jonathan K., Leroux-Roels, Geert, Pietschmann, Thomas, Nicosia, Alfredo, Meuleman, Philip, Vercauteren, Koen, Brown, Richard J.P., Mesalam, Ahmed Atef, Doerrbecker, Juliane, Bhuju, Sabin, Geffers, Robert, Van Den Eede, Naomi, McClure, C. Patrick, Troise, Fulvia, Verhoye, Lieven, Baumert, Thomas, Farhoudi, Ali, Cortese, Riccardo, Ball, Jonathan K., Leroux-Roels, Geert, Pietschmann, Thomas, Nicosia, Alfredo, and Meuleman, Philip
- Abstract
Objective: Direct-acting antivirals (DAAs) inhibit hepatitis C virus (HCV) infection by targeting viral proteins that play essential roles in the replication process. However, selection of resistance-associated variants (RAVs) during DAA therapy has been a cause of therapeutic failure. In this study, we wished to address whether such RAVs could be controlled by the co-administration of host-targeting entry inhibitors that prevent intrahepatic viral spread. Design: We investigated the effect of adding an entry inhibitor (the anti-scavenger receptor class B type I mAb1671) to a DAA monotherapy (the protease inhibitor ciluprevir) in human-liver mice chronically infected with HCV of genotype 1b. Clinically relevant non-laboratory strains were used to achieve viraemia consisting of a cloud of related viral variants (quasispecies) and the emergence of RAVs was monitored at high resolution using next-generation sequencing. Results: HCV-infected human-liver mice receiving DAA monotherapy rapidly experienced on-therapy viral breakthrough. Deep sequencing of the HCV protease domain confirmed the manifestation of drug-resistant mutants upon viral rebound. In contrast, none of the mice treated with a combination of the DAA and the entry inhibitor experienced on-therapy viral breakthrough, despite detection of RAV emergence in some animals. Conclusions: This study provides preclinical in vivo evidence that addition of an entry inhibitor to an anti-HCV DAA regimen restricts the breakthrough of DAA-resistant viruses. Our approach is an excellent strategy to prevent therapeutic failure caused by on-therapy rebound of DAA-RAVs. Inclusion of an entry inhibitor to the newest DAA combination therapies may further increase response rates, especially in difficult-to-treat patient populations.
- Full Text
- View/download PDF
36. A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo
- Author
-
Desombere, Isabelle, Mesalam, Ahmed Atef, Urbanowicz, Richard A., Van Houtte, Freya, Verhoye, Lieven, Keck, Zhen-Yong, Farhoudi, Ali, Vercauteren, Koen, Weening, Karin E., Baumert, Thomas F., Patel, Arvind H., Foung, Steven K.H., Ball, Jonathan, Leroux-Roels, Geert, Meuleman, Philip, Desombere, Isabelle, Mesalam, Ahmed Atef, Urbanowicz, Richard A., Van Houtte, Freya, Verhoye, Lieven, Keck, Zhen-Yong, Farhoudi, Ali, Vercauteren, Koen, Weening, Karin E., Baumert, Thomas F., Patel, Arvind H., Foung, Steven K.H., Ball, Jonathan, Leroux-Roels, Geert, and Meuleman, Philip
- Abstract
Infections with hepatitis C virus (HCV) represent a worldwide health burden and a prophylactic vaccine is still not available. Liver transplantation (LT) is often the only option for patients with HCV-induced end-stage liver disease. However, immediately after transplantation, the liver graft becomes infected by circulating virus, resulting in accelerated progression of liver disease. Although the effi cacy of HCV treatment using direct-acting antivirals has improved significantly, immune compromised LT-patients and patients with advanced liver disease remain difficult to treat. As an alternative approach, interfering with viral entry could prevent infection of the donor liver. We generated a human monoclonal antibody (mAb), designated 2A5, which targets the HCV envelope. The neutralizing activity of mAb 2A5 was assessed using multiple prototype and patient-derived HCV pseudoparticles (HCVpp), cell culture produced HCV (HCVcc), and a human-liver chimeric mouse model. Neutralization levels observed for mAb 2A5 were generally high and mostly superior to those obtained with AP33, a well-characterized HCV-neutralizing monoclonal antibody. Using humanized mice, complete protection was observed after genotype 1a and 4a HCV challenge, while only partial protection was achieved using gt1b and 6a isolates. Epitope mapping revealed that mAb 2A5 binding is conformation-dependent and identified the E2-region spanning amino acids 434 to 446 (epitope II) as the predominant contact domain. Conclusion : mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence represent a valuable candidate to prevent HCV recurrence in LT-patients. In addition, the detailed identification of the neutralizing epitope can be applied for the design of prophylactic HCV vaccines.
- Full Text
- View/download PDF
37. Development and characterization of a human monoclonal antibody targeting the N-terminal region of hepatitis C virus envelope glycoprotein E1
- Author
-
Mesalam, Ahmed Atef, Desombere, Isabelle, Farhoudi, Ali, Van Houtte, Freya, Verhoye, Lieven, Ball, Jonathan, Dubuisson, Jean, Foung, Steven K.H., Patel, Arvind H., Persson, Mats A.A., Leroux-Roels, Geert, Meuleman, Philip, Mesalam, Ahmed Atef, Desombere, Isabelle, Farhoudi, Ali, Van Houtte, Freya, Verhoye, Lieven, Ball, Jonathan, Dubuisson, Jean, Foung, Steven K.H., Patel, Arvind H., Persson, Mats A.A., Leroux-Roels, Geert, and Meuleman, Philip
- Abstract
Monoclonal antibodies (mAbs) targeting the hepatitis C virus (HCV) envelope have been raised mainly against envelope protein 2 (E2), while the antigenic epitopes of envelope protein 1 (E1) are not fully identified. Here we describe the detailed characterization of a human mAb, designated A6, generated from an HCV genotype 1b infected patient. ELISA results showed reactivity of mAb A6 to full-length HCV E1E2 of genotypes 1a, 1b and 2a. Epitope mapping identified a region spanning amino acids 230-239 within the N-terminal region of E1 as critical for binding. Antibody binding to this epitope was not conformation dependent. Neutralization assays showed that mAb A6 lacks neutralizing capacity and does not interfere with the activity of known neutralizing antibodies. In summary, mAb A6 is an important tool to study the structure and function of E1 within the viral envelope, a crucial step in the development of an effective prophylactic HCV vaccine.
- Full Text
- View/download PDF
38. Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice
- Author
-
Vercauteren, Koen, Brown, Richard J.P., Mesalam, Ahmed Atef, Doerrbecker, Juliane, Bhuju, Sabin, Geffers, Robert, Van Den Eede, Naomi, McClure, C. Patrick, Troise, Fulvia, Verhoye, Lieven, Baumert, Thomas, Farhoudi, Ali, Cortese, Riccardo, Ball, Jonathan K., Leroux-Roels, Geert, Pietschmann, Thomas, Nicosia, Alfredo, Meuleman, Philip, Vercauteren, Koen, Brown, Richard J.P., Mesalam, Ahmed Atef, Doerrbecker, Juliane, Bhuju, Sabin, Geffers, Robert, Van Den Eede, Naomi, McClure, C. Patrick, Troise, Fulvia, Verhoye, Lieven, Baumert, Thomas, Farhoudi, Ali, Cortese, Riccardo, Ball, Jonathan K., Leroux-Roels, Geert, Pietschmann, Thomas, Nicosia, Alfredo, and Meuleman, Philip
- Abstract
Objective: Direct-acting antivirals (DAAs) inhibit hepatitis C virus (HCV) infection by targeting viral proteins that play essential roles in the replication process. However, selection of resistance-associated variants (RAVs) during DAA therapy has been a cause of therapeutic failure. In this study, we wished to address whether such RAVs could be controlled by the co-administration of host-targeting entry inhibitors that prevent intrahepatic viral spread. Design: We investigated the effect of adding an entry inhibitor (the anti-scavenger receptor class B type I mAb1671) to a DAA monotherapy (the protease inhibitor ciluprevir) in human-liver mice chronically infected with HCV of genotype 1b. Clinically relevant non-laboratory strains were used to achieve viraemia consisting of a cloud of related viral variants (quasispecies) and the emergence of RAVs was monitored at high resolution using next-generation sequencing. Results: HCV-infected human-liver mice receiving DAA monotherapy rapidly experienced on-therapy viral breakthrough. Deep sequencing of the HCV protease domain confirmed the manifestation of drug-resistant mutants upon viral rebound. In contrast, none of the mice treated with a combination of the DAA and the entry inhibitor experienced on-therapy viral breakthrough, despite detection of RAV emergence in some animals. Conclusions: This study provides preclinical in vivo evidence that addition of an entry inhibitor to an anti-HCV DAA regimen restricts the breakthrough of DAA-resistant viruses. Our approach is an excellent strategy to prevent therapeutic failure caused by on-therapy rebound of DAA-RAVs. Inclusion of an entry inhibitor to the newest DAA combination therapies may further increase response rates, especially in difficult-to-treat patient populations.
- Full Text
- View/download PDF
39. A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo
- Author
-
Desombere, Isabelle, Mesalam, Ahmed Atef, Urbanowicz, Richard A., Van Houtte, Freya, Verhoye, Lieven, Keck, Zhen-Yong, Farhoudi, Ali, Vercauteren, Koen, Weening, Karin E., Baumert, Thomas F., Patel, Arvind H., Foung, Steven K.H., Ball, Jonathan, Leroux-Roels, Geert, Meuleman, Philip, Desombere, Isabelle, Mesalam, Ahmed Atef, Urbanowicz, Richard A., Van Houtte, Freya, Verhoye, Lieven, Keck, Zhen-Yong, Farhoudi, Ali, Vercauteren, Koen, Weening, Karin E., Baumert, Thomas F., Patel, Arvind H., Foung, Steven K.H., Ball, Jonathan, Leroux-Roels, Geert, and Meuleman, Philip
- Abstract
Infections with hepatitis C virus (HCV) represent a worldwide health burden and a prophylactic vaccine is still not available. Liver transplantation (LT) is often the only option for patients with HCV-induced end-stage liver disease. However, immediately after transplantation, the liver graft becomes infected by circulating virus, resulting in accelerated progression of liver disease. Although the effi cacy of HCV treatment using direct-acting antivirals has improved significantly, immune compromised LT-patients and patients with advanced liver disease remain difficult to treat. As an alternative approach, interfering with viral entry could prevent infection of the donor liver. We generated a human monoclonal antibody (mAb), designated 2A5, which targets the HCV envelope. The neutralizing activity of mAb 2A5 was assessed using multiple prototype and patient-derived HCV pseudoparticles (HCVpp), cell culture produced HCV (HCVcc), and a human-liver chimeric mouse model. Neutralization levels observed for mAb 2A5 were generally high and mostly superior to those obtained with AP33, a well-characterized HCV-neutralizing monoclonal antibody. Using humanized mice, complete protection was observed after genotype 1a and 4a HCV challenge, while only partial protection was achieved using gt1b and 6a isolates. Epitope mapping revealed that mAb 2A5 binding is conformation-dependent and identified the E2-region spanning amino acids 434 to 446 (epitope II) as the predominant contact domain. Conclusion : mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence represent a valuable candidate to prevent HCV recurrence in LT-patients. In addition, the detailed identification of the neutralizing epitope can be applied for the design of prophylactic HCV vaccines.
- Full Text
- View/download PDF
40. Development and characterization of a human monoclonal antibody targeting the N-terminal region of hepatitis C virus envelope glycoprotein E1
- Author
-
Mesalam, Ahmed Atef, Desombere, Isabelle, Farhoudi, Ali, Van Houtte, Freya, Verhoye, Lieven, Ball, Jonathan, Dubuisson, Jean, Foung, Steven K.H., Patel, Arvind H., Persson, Mats A.A., Leroux-Roels, Geert, Meuleman, Philip, Mesalam, Ahmed Atef, Desombere, Isabelle, Farhoudi, Ali, Van Houtte, Freya, Verhoye, Lieven, Ball, Jonathan, Dubuisson, Jean, Foung, Steven K.H., Patel, Arvind H., Persson, Mats A.A., Leroux-Roels, Geert, and Meuleman, Philip
- Abstract
Monoclonal antibodies (mAbs) targeting the hepatitis C virus (HCV) envelope have been raised mainly against envelope protein 2 (E2), while the antigenic epitopes of envelope protein 1 (E1) are not fully identified. Here we describe the detailed characterization of a human mAb, designated A6, generated from an HCV genotype 1b infected patient. ELISA results showed reactivity of mAb A6 to full-length HCV E1E2 of genotypes 1a, 1b and 2a. Epitope mapping identified a region spanning amino acids 230-239 within the N-terminal region of E1 as critical for binding. Antibody binding to this epitope was not conformation dependent. Neutralization assays showed that mAb A6 lacks neutralizing capacity and does not interfere with the activity of known neutralizing antibodies. In summary, mAb A6 is an important tool to study the structure and function of E1 within the viral envelope, a crucial step in the development of an effective prophylactic HCV vaccine.
- Full Text
- View/download PDF
41. Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice
- Author
-
Vercauteren, Koen, Brown, Richard J.P., Mesalam, Ahmed Atef, Doerrbecker, Juliane, Bhuju, Sabin, Geffers, Robert, Van Den Eede, Naomi, McClure, C. Patrick, Troise, Fulvia, Verhoye, Lieven, Baumert, Thomas, Farhoudi, Ali, Cortese, Riccardo, Ball, Jonathan K., Leroux-Roels, Geert, Pietschmann, Thomas, Nicosia, Alfredo, Meuleman, Philip, Vercauteren, Koen, Brown, Richard J.P., Mesalam, Ahmed Atef, Doerrbecker, Juliane, Bhuju, Sabin, Geffers, Robert, Van Den Eede, Naomi, McClure, C. Patrick, Troise, Fulvia, Verhoye, Lieven, Baumert, Thomas, Farhoudi, Ali, Cortese, Riccardo, Ball, Jonathan K., Leroux-Roels, Geert, Pietschmann, Thomas, Nicosia, Alfredo, and Meuleman, Philip
- Abstract
Objective: Direct-acting antivirals (DAAs) inhibit hepatitis C virus (HCV) infection by targeting viral proteins that play essential roles in the replication process. However, selection of resistance-associated variants (RAVs) during DAA therapy has been a cause of therapeutic failure. In this study, we wished to address whether such RAVs could be controlled by the co-administration of host-targeting entry inhibitors that prevent intrahepatic viral spread. Design: We investigated the effect of adding an entry inhibitor (the anti-scavenger receptor class B type I mAb1671) to a DAA monotherapy (the protease inhibitor ciluprevir) in human-liver mice chronically infected with HCV of genotype 1b. Clinically relevant non-laboratory strains were used to achieve viraemia consisting of a cloud of related viral variants (quasispecies) and the emergence of RAVs was monitored at high resolution using next-generation sequencing. Results: HCV-infected human-liver mice receiving DAA monotherapy rapidly experienced on-therapy viral breakthrough. Deep sequencing of the HCV protease domain confirmed the manifestation of drug-resistant mutants upon viral rebound. In contrast, none of the mice treated with a combination of the DAA and the entry inhibitor experienced on-therapy viral breakthrough, despite detection of RAV emergence in some animals. Conclusions: This study provides preclinical in vivo evidence that addition of an entry inhibitor to an anti-HCV DAA regimen restricts the breakthrough of DAA-resistant viruses. Our approach is an excellent strategy to prevent therapeutic failure caused by on-therapy rebound of DAA-RAVs. Inclusion of an entry inhibitor to the newest DAA combination therapies may further increase response rates, especially in difficult-to-treat patient populations.
- Full Text
- View/download PDF
42. Functional study of the C-terminal part of hepatitis C virus E1 ectodomain.
- Author
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Moustafa, Rehab I., Haddad, Juliano G., Linna, Lydia, Hanoulle, Xavier, Descamps, Véronique, Mesalam, Ahmed Atef, Baumert, Thomas F., Duverlie, Gilles, Meuleman, Philip, Dubuisson, Jean, and Lavie, Muriel
- Subjects
- *
HEPATITIS C virus , *GLYCOPROTEINS , *HETERODIMERS , *CARRIER proteins , *HYDROPHOBIC compounds - Abstract
In the HCV envelope glycoproteins E1 and E2, which form a heterodimer, E2 is the receptor binding protein and the major target of neutralizing antibodies, whereas the function of E1 remains less characterized. To investigate E1 functions, we generated a series of mutants in the conserved residues of the C-terminal region of the E1 ectodomain in the context of an infectious clone. We focused our analyses on two regions of interest. The first region is located in the middle of the E1 glycoprotein (between amino acids (aa) 270 and 291), which contains a conserved hydrophobic sequence and was proposed to constitute a putative fusion peptide. The second series of mutants was generated in the aa314-342 region, which has been shown to contain two alpha helices (α2 and α3) by NMR studies. Twenty out of the twenty-two generated mutants were either attenuated or noninfectious. Several mutations modulated the virus's dependence on claudin-1 and the scavenger receptor BI co-receptors for entry. Most of the mutations in the putative fusion peptide region affected virus assembly. Conversely, mutations in the α-helix 315-324 residues M318, W320, D321, and M322 resulted in a complete loss of infectivity without any impact on E1E2 folding and on viral assembly. Further characterization of the W320A mutant in the HCVpp model indicated that the loss of infectivity was due to a defect in viral entry. Together, these results support a role for E1 in modulating HCV interaction with its co-receptors and in HCV assembly. They also highlight the involvement of α-helix 315-324 in a late step of HCV entry. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
43. Successful anti-scavenger receptor class B type I (SR-BI) monoclonal antibody therapy in humanized mice after challenge with HCV variants within vitroresistance to SR-BI-targeting agents
- Author
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Dorothea Bankwitz, Alfredo Nicosia, Charles M. Rice, Maria Teresa Catanese, Sandrine Belouzard, Flossie Wong-Staal, Jean Dubuisson, Ahmed Atef Ahmed Abouzeid Mesalam, Riccardo Cortese, Naomi Van den Eede, Koen Vercauteren, Thomas Pietschmann, Geert Leroux-Roels, Philip Meuleman, Vercauteren, Koen, Van Den Eede, Naomi, Mesalam, Ahmed Atef, Belouzard, Sandrine, Catanese, Maria Teresa, Bankwitz, Dorothea, Wong Staal, Flossie, Cortese, Riccardo, Dubuisson, Jean, Rice, Charles M., Pietschmann, Thoma, Leroux Roels, Geert, Nicosia, Alfredo, and Meuleman, Philip
- Subjects
medicine.drug_class ,Lipoproteins ,Hepatitis C virus ,Hepacivirus ,Mice, SCID ,Biology ,medicine.disease_cause ,Monoclonal antibody ,Article ,Virus ,Liver disease ,Triiodobenzoic Acids ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Scavenger receptor ,Lipoprotein ,Monoclonal antibody therapy ,Hepaciviru ,Hepatology ,Animal ,Medicine (all) ,Editorials ,virus diseases ,Antibodies, Monoclonal ,Triiodobenzoic Acid ,Scavenger Receptors, Class B ,medicine.disease ,Hepatitis C ,Virology ,digestive system diseases ,Transplantation ,Treatment Outcome ,Immunology ,biology.protein ,Antibody ,Human - Abstract
Hepatitis C virus (HCV)-induced endstage liver disease is currently a major indication for liver transplantation. After transplantation the donor liver inevitably becomes infected with the circulating virus. Monoclonal antibodies (mAbs) against the HCV coreceptor scavenger receptor class B type I (SR-BI) inhibit HCV infection of different genotypes, both in cell culture and in humanized mice. Anti-SR-BI mAb therapy is successful even when initiated several days after HCV exposure, supporting its potential applicability to prevent HCV reinfection of liver allografts. However, HCV variants with reduced SR-BI dependency have been described in the literature, which could potentially limit the use of SR-BI targeting therapy. In this study we show, both in a preventative and postexposure setting, that humanized mice infected with HCV variants exhibiting increased in vitro resistance to SR-BI-targeting molecules remain responsive to anti-SR-BI mAb therapy in vivo. A 2-week antibody therapy readily cleared HCV RNA from the circulation of infected humanized mice. We found no evidence supporting increased SR-BI-receptor dependency of viral particles isolated from humanized mice compared to cell culture-produced virus. However, we observed that, unlike wild-type virus, the in vitro infectivity of the resistant variants was inhibited by both human high density lipoprotein (HDL) and very low density lipoprotein (VLDL). The combination of mAb1671 with these lipoproteins further increased the antiviral effect. Conclusion: HCV variants that are less dependent on SR-BI in vitro can still be efficiently blocked by an anti-SR-BI mAb in humanized mice. Since these variants are also more susceptible to neutralization by anti-HCV envelope antibodies, their chance of emerging during anti-SR-BI therapy is severely reduced. Our data indicate that anti-SR-BI receptor therapy could be an effective way to prevent HCV infection in a liver transplant setting. (Hepatology 2014;60:1508–1518)
- Published
- 2014
44. Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice
- Author
-
Robert Geffers, Alfredo Nicosia, Thomas F. Baumert, Lieven Verhoye, Fulvia Troise, Jonathan K. Ball, Sabin Bhuju, Riccardo Cortese, Ali Farhoudi, Philip Meuleman, Ahmed Atef Ahmed Abouzeid Mesalam, Koen Vercauteren, Juliane Doerrbecker, Naomi Van den Eede, Richard J. C. Brown, Geert Leroux-Roels, Thomas Pietschmann, C. Patrick McClure, Vercauteren, Koen, Brown, Richard J. P., Mesalam, Ahmed Atef, Doerrbecker, Juliane, Bhuju, Sabin, Geffers, Robert, Van Den Eede, Naomi, Mcclure, C. Patrick, Troise, Fulvia, Verhoye, Lieven, Baumert, Thoma, Farhoudi, Ali, Cortese, Riccardo, Ball, Jonathan K., Leroux-Roels, Geert, Pietschmann, Thoma, Nicosia, Alfredo, and Meuleman, Philip
- Subjects
0301 basic medicine ,LIVER ,Genotype ,Hepatitis C virus ,Protease Inhibitor ,Mutation, Missense ,CHRONIC VIRAL HEPATITIS ,Hepacivirus ,Viral quasispecies ,Viral Nonstructural Proteins ,medicine.disease_cause ,Antiviral Agents ,Deep sequencing ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Ciluprevir ,Drug Resistance, Viral ,medicine ,Animals ,Protease Inhibitors ,Protease inhibitor (pharmacology) ,Antiviral Agent ,Hepaciviru ,business.industry ,Animal ,Viral Nonstructural Protein ,Gastroenterology ,Hepatitis C ,Hepatitis C, Chronic ,medicine.disease ,ANTIVIRAL THERAPY ,Virology ,Viral Breakthrough ,3. Good health ,Entry inhibitor ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Amino Acid Substitution ,Immunology ,HCV ,HEPATITIS C ,business ,medicine.drug - Abstract
Objective: Direct-acting antivirals (DAAs) inhibit hepatitis C virus (HCV) infection by targeting viral proteins that play essential roles in the replication process. However, selection of resistance-associated variants (RAVs) during DAA therapy has been a cause of therapeutic failure. In this study, we wished to address whether such RAVs could be controlled by the co-administration of host-targeting entry inhibitors that prevent intrahepatic viral spread. Design: We investigated the effect of adding an entry inhibitor (the anti-scavenger receptor class B type I mAb1671) to a DAA monotherapy (the protease inhibitor ciluprevir) in human-liver mice chronically infected with HCV of genotype 1b. Clinically relevant non-laboratory strains were used to achieve viraemia consisting of a cloud of related viral variants (quasispecies) and the emergence of RAVs was monitored at high resolution using next-generation sequencing. Results: HCV-infected human-liver mice receiving DAA monotherapy rapidly experienced on-therapy viral breakthrough. Deep sequencing of the HCV protease domain confirmed the manifestation of drug-resistant mutants upon viral rebound. In contrast, none of the mice treated with a combination of the DAA and the entry inhibitor experienced on-therapy viral breakthrough, despite detection of RAV emergence in some animals. Conclusions: This study provides preclinical in vivo evidence that addition of an entry inhibitor to an anti-HCV DAA regimen restricts the breakthrough of DAA-resistant viruses. Our approach is an excellent strategy to prevent therapeutic failure caused by on-therapy rebound of DAA-RAVs. Inclusion of an entry inhibitor to the newest DAA combination therapies may further increase response rates, especially in difficult-to-treat patient populations.
- Published
- 2016
45. A human monoclonal antibody against HBsAg for the prevention and treatment of chronic HBV and HDV infection.
- Author
-
Burm R, Van Houtte F, Verhoye L, Mesalam AA, Ciesek S, Roingeard P, Wedemeyer H, Leroux-Roels G, and Meuleman P
- Abstract
Background & Aims: Elimination of chronic HBV/HDV infection remains a major global health challenge. Targeting excessive hepatitis B surface antigen (HBsAg) release may provide an interesting window of opportunity to break immune tolerance and to achieve a functional cure using additional antivirals., Methods: We evaluated a HBsAg-specific human monoclonal antibody, as part of either a prophylactic or therapeutic strategy, against HBV/HDV infection in cell culture models and in human-liver chimeric mice. To assess prophylactic efficacy, mice were passively immunized prior to infection with HBV or HBV/HDV (coinfection and superinfection setting). Therapeutic efficacy was assessed in HBV and HBV/HDV-coinfected mice receiving 4 weeks of treatment. Viral parameters (HBV DNA, HDV RNA and HBsAg) were assessed in mouse plasma., Results: The antibody could effectively prevent HBV/HDV infection in a dose-dependent manner with IC
50 values of ∼3.5 ng/ml. Passive immunization showed complete protection of mice from both HBV and HBV/HDV coinfection. Moreover, HDV superinfection was either completely prevented or at least attenuated in HBV-infected mice. Finally, antibody treatment in mice with established HBV/HDV infection resulted in a significant decline in viremia and a concomitant drop in on-treatment HBsAg, with a moderate viral rebound following treatment cessation., Conclusion: We present data on a valuable antibody candidate that could complement other antivirals in strategies aimed at achieving functional cure of chronic HBV and HDV infection., Impact and Implications: Patients chronically infected with HBV may eventually develop liver cancer and are at great risk of being superinfected with HDV, which worsens and accelerates disease progression. Unfortunately, current treatments can rarely eliminate both viruses from chronically infected patients. In this study, we present data on a novel antibody that is able to prevent chronic HBV/HDV infection in a mouse model with a humanized liver. Moreover, antibody treatment of HBV/HDV-infected mice strongly diminishes viral loads during therapy. This antibody is a valuable candidate for further clinical development., Competing Interests: Nothing to declare related to the content of this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Authors.)- Published
- 2022
- Full Text
- View/download PDF
46. Development and characterization of a human monoclonal antibody targeting the N-terminal region of hepatitis C virus envelope glycoprotein E1.
- Author
-
Mesalam AA, Desombere I, Farhoudi A, Van Houtte F, Verhoye L, Ball J, Dubuisson J, Foung SKH, Patel AH, Persson MAA, Leroux-Roels G, and Meuleman P
- Subjects
- Antibodies, Monoclonal analysis, Antibodies, Neutralizing analysis, Epitope Mapping, Genotype, Hepacivirus chemistry, Hepacivirus genetics, Hepatitis C genetics, Humans, Viral Envelope Proteins chemistry, Viral Envelope Proteins genetics, Antibodies, Monoclonal immunology, Antibodies, Neutralizing immunology, Hepacivirus immunology, Hepatitis C immunology, Viral Envelope Proteins immunology
- Abstract
Monoclonal antibodies (mAbs) targeting the hepatitis C virus (HCV) envelope have been raised mainly against envelope protein 2 (E2), while the antigenic epitopes of envelope protein 1 (E1) are not fully identified. Here we describe the detailed characterization of a human mAb, designated A6, generated from an HCV genotype 1b infected patient. ELISA results showed reactivity of mAb A6 to full-length HCV E1E2 of genotypes 1a, 1b and 2a. Epitope mapping identified a region spanning amino acids 230-239 within the N-terminal region of E1 as critical for binding. Antibody binding to this epitope was not conformation dependent. Neutralization assays showed that mAb A6 lacks neutralizing capacity and does not interfere with the activity of known neutralizing antibodies. In summary, mAb A6 is an important tool to study the structure and function of E1 within the viral envelope, a crucial step in the development of an effective prophylactic HCV vaccine., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
47. Mouse Systems to Model Hepatitis C Virus Treatment and Associated Resistance.
- Author
-
Mesalam AA, Vercauteren K, and Meuleman P
- Subjects
- Animals, Drug Evaluation, Preclinical methods, Humans, Mice, Pan troglodytes, Antiviral Agents administration & dosage, Disease Models, Animal, Drug Resistance, Viral, Hepacivirus drug effects, Hepatitis C drug therapy, Hepatitis C virology
- Abstract
While addition of the first-approved protease inhibitors (PIs), telaprevir and boceprevir, to pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy significantly increased sustained virologic response (SVR) rates, PI-based triple therapy for the treatment of chronic hepatitis C virus (HCV) infection was prone to the emergence of resistant viral variants. Meanwhile, multiple direct acting antiviral agents (DAAs) targeting either the HCV NS3/4A protease, NS5A or NS5B polymerase have been approved and these have varying potencies and distinct propensities to provoke resistance. The pre-clinical in vivo assessment of drug efficacy and resistant variant emergence underwent a great evolution over the last decade. This field had long been hampered by the lack of suitable small animal models that robustly support the entire HCV life cycle. In particular, chimeric mice with humanized livers (humanized mice) and chimpanzees have been instrumental for studying HCV inhibitors and the evolution of drug resistance. In this review, we present the different in vivo HCV infection models and discuss their applicability to assess HCV therapy response and emergence of resistant variants.
- Published
- 2016
- Full Text
- View/download PDF
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