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Viral Hepatitis
Hepatitis B surface antigen genetic elements critical for immune escape correlate with hepatitis B virus reactivation upon immunosuppression
Romina Salpini1,
Luna Colagrossi1,
Maria Concetta Bellocchi1,
Matteo Surdo1,
Christina Becker2,
Claudia Alteri1,
Marianna Aragri1,
Alessandra Ricciardi3,
Daniele Armenia1,
Michela Pollicita1,
Fabiola Di Santo1,
Luca Carioti1,
Yoram Louzoun4,
Claudio Maria Mastroianni5,
Miriam Lichtner5,
Maurizio Paoloni6,
Mariarosaria Esposito7,
Chiara D'Amore8,
Aldo Marrone8,
Massimo Marignani9,
Cesare Sarrecchia3,
Loredana Sarmati3,
Massimo Andreoni3,
Mario Angelico10,
Jens Verheyen11,†,
Carlo-Federico Perno1,* and
Valentina Svicher1,*
Article first published online: 28 JAN 2015
DOI: 10.1002/hep.27604
© 2014 by the American Association for the Study of Liver Diseases
Issue
Hepatology
Hepatology
Volume 61, Issue 3, pages 823–833, March 2015
Additional Information(Show All)
How to CiteAuthor InformationPublication History
Author Information
1 Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
2 Institute of Virology, University of Cologne, Cologne, Germany
3 Infectious Diseases Unit, Tor Vergata University Hospital, Rome, Italy
4 Department of Mathematics and Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel
5 Sapienza University, Polo Pontino, Latina, Italy
6 Infectious Disease Unit, “S.S. Filippo e Nicola” Hospital, Avezzano, Italy
7 Hematology Unit, San Gennaro Hospital of Naples, Naples, Italy
8 Internal Medicine and Hepatology Unit, Second University of Naples, Naples, Italy
9 S. Andrea” Hospital, Rome, Italy
10 Hepatology Unit, Tor Vergata University Hospital, Rome, Italy
11 Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
†
[Correction added on February 9, 2015, after first online publication: In original publication, Jens Verheyen's name was incorrectly spelled as Verhejen, and his affiliation incorrectly given as University of Essen.]
*Address reprint requests to: Carlo Federico Perno, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. E-mail: [email protected]; fax: +0039 06 72596039 or Valentina Svicher, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. E-mail: [email protected]; fax: +0039 06 72596039.
Potential conflict of interest: Dr. Andreoni consults and received grants from Gilead, Bristol-Myers Squibb, Viiv, Janssen, and Merck. Dr. Angelico consults for, is on the speakers' bureau of, and received grants from Gilead. He is on the speakers' bureau for Roche. He received grants from AbbVie, Bristol-Myers Squibb, and Janssen. Dr. Verhejen is on the speakers' bureau for Siemens and Janssen and received grants from Abbott. Dr. Perno consults for and received grants from Viiv, Bristol-Myers Squibb, Gilead, Janssen, Merck, and AbbVie. Dr. Svicher received grants from Bristol-Myers Squibb, Gilead, and Roche.
This work was supported by the FIRB project (RBAP11YS7K_001), by the Italian Ministry of Instruction, University and Research (Progetto Bandiera PB05), the Aviralia Foundation, and by financial support from the Bristol-Myers Squibb Partnering for Cure Research Program 2013.
Hepatitis B virus (HBV) reactivation during immunosuppression can lead to severe acute hepatitis, fulminant liver failure, and death. Here, we investigated hepatitis B surface antigen (HBsAg) genetic features underlying this phenomenon by analyzing 93 patients: 29 developing HBV reactivation and 64 consecutive patients with chronic HBV infection (as control). HBsAg genetic diversity was analyzed by population-based and ultradeep sequencing (UDS). Before HBV reactivation, 51.7% of patients were isolated hepatitis B core antibody (anti-HBc) positive, 31.0% inactive carriers, 6.9% anti-HBc/anti-HBs (hepatitis B surface antibody) positive, 6.9% isolated anti-HBs positive, and 3.4% had an overt HBV infection. Of HBV-reactivated patients, 51.7% were treated with rituximab, 34.5% with different chemotherapeutics, and 13.8% with corticosteroids only for inflammatory diseases. In total, 75.9% of HBV-reactivated patients (vs. 3.1% of control patients; P < 0.001) carried HBsAg mutations localized in immune-active HBsAg regions. Of the 13 HBsAg mutations found in these patients, 8 of 13 (M103I-L109I-T118K-P120A-Y134H-S143L-D144E-S171F) reside in a major hydrophilic loop (target of neutralizing antibodies [Abs]); some of them are already known to hamper HBsAg recognition by humoral response. The remaining five (C48G-V96A-L175S-G185E-V190A) are localized in class I/II–restricted T-cell epitopes, suggesting a role in HBV escape from T-cell-mediated responses. By UDS, these mutations occurred in HBV-reactivated patients with a median intrapatient prevalence of 73.3% (range, 27.6%-100%) supporting their fixation in the viral population as a predominant species. In control patients carrying such mutations, their median intrapatient prevalence was 4.6% (range, 2.5%-11.3%; P < 0.001). Finally, additional N-linked glycosylation (NLG) sites within the major hydrophilic loop were found in 24.1% of HBV-reactivated patients (vs. 0% of chronic patients; P < 0.001); 5 of 7 patients carrying these sites remained HBsAg negative despite HBV reactivation. NLG can mask immunogenic epitopes, abrogating HBsAg recognition by Abs. Conclusion: HBV reactivation occurs in a wide variety of clinical settings requiring immune-suppressive therapy, and correlates with HBsAg mutations endowed with enhanced capability to evade immune response. This highlights the need for careful patient monitoring in all immunosuppressive settings at reactivation risk and of establishing a prompt therapy to prevent HBV-related clinical complications. (Hepatology 2015;61:823–833)
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发表于 2015-3-22 08:55
