Multiple Hepatitis B Virus (HBV) Quasispecies and Immune-Escape Mutations Are Present in HBV Surface Antigen and Reverse Transcriptase of Patients With Acute Hepatitis B - Marianna Aragri1,a,
- Claudia Alteri1,a,
- Arianna Battisti1,
- Domenico Di Carlo1,
- Carmine Minichini2,
- Caterina Sagnelli3,
- Maria Concetta Bellocchi1,
- Maria Antonietta Pisaturo2,
- Mario Starace2,
- Daniele Armenia1,
- Luca Carioti1,
- Michela Pollicita1,
- Romina Salpini1,
- Evangelista Sagnelli2,
- Carlo Federico Perno1,
- Nicola Coppola2,b and
- Valentina Svicher1,b
- 1Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome
- 2Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Caserta
- 3Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Italy
- Correspondence: V. Svicher, Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy (valentina.svicher{at}uniroma2.it).
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Presented in part: Conference on Retroviruses and Opportunistic Infection, Seattle, Washington, 23–26 February 2015. Poster P702; Association for the Study of the Liver—Annual Meeting 2015, Rome, Italy, 19–20 February 2015. Poster P15; The International Liver Congress EASL, Vienna, Austria, 22–26 April 2015. Poster P628; 13th EU HIV and Hepatitis Workshop, Barcelona, Spain, 3–5 June 2015. Poster P71. -
↵a M. A. and C. A. contributed equally to this study. -
↵b N. C. and V. S. are joint final authors.
Abstract Background. This study characterizes and defines the clinical value of hepatitis B virus (HBV) quasispecies with reverse transcriptase and HBV surface antigen (HBsAg) heterogeneity in patients with acute HBV infection. Methods. Sixty-two patients with acute HBV infection (44 with genotype D infection and 18 with genotype A infection) were enrolled from 2000 to 2010. Plasma samples obtained at the time of the first examination were analyzed by ultradeep pyrosequencing. The extent of HBsAg amino acid variability was measured by Shannon entropy. Results. Median alanine aminotransferase and serum HBV DNA levels were 2544 U/L (interquartile range, 1938–3078 U/L) and 5.88 log10 IU/mL (interquartile range, 4.47–7.37 log10 IU/mL), respectively. Although most patients serologically resolved acute HBV infection, only 54.1% developed antibody to HBsAg (anti-HBs). A viral population with ≥1 immune-escape mutation was found in 53.2% of patients (intrapatient prevalence range, 0.16%–100%). Notably, by Shannon entropy, higher genetic variability at HBsAg amino acid positions 130, 133, and 157 significantly correlated with no production of anti-HBs in individuals infected with genotype D (P < .05). Stop codons were detected in 19.3% of patients (intrapatient prevalence range, 1.6%–47.5%) and occurred at 11 HBsAg amino acid positions, including 172 and 182, which are known to increase the oncogenic potential of HBV. Finally, ≥1 drug resistance mutation was detected in 8.1% of patients (intrapatient prevalence range, 0.11%–47.5% for primary mutations and 10.5%–99.9% for compensatory mutations). Conclusions. Acute HBV infection is characterized by complex array of viral quasispecies with reduced antigenicity/immunogenicity and enhanced oncogenic potential. These viral variants may induce difficult-to-treat HBV forms; favor HBV reactivation upon iatrogenic immunosuppression, even years after infection; and potentially affect the efficacy of the current HBV vaccination strategy.
Key words - Received November 4, 2015.
- Accepted January 28, 2016.
- © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions{at}oup.com
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发表于 2016-5-25 18:29