title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome.
authors.forename: Marianna
authors.initials: M
authors.lastname: Aragri
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome.
authors.forename: Claudia
authors.initials: C
authors.lastname: Alteri
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome.
authors.forename: Arianna
authors.initials: A
authors.lastname: Battisti
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome.
authors.forename: Domenico
authors.initials: D
authors.lastname: Di Carlo
authors.affiliation: Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Caserta.
authors.forename: Carmine
authors.initials: C
authors.lastname: Minichini
authors.affiliation: Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Sagnelli
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome.
authors.forename: Maria Concetta
authors.initials: MC
authors.lastname: Bellocchi
authors.affiliation: Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Caserta.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Pisaturo
authors.affiliation: Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Caserta.
authors.forename: Mario
authors.initials: M
authors.lastname: Starace
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome.
authors.forename: Daniele
authors.initials: D
authors.lastname: Armenia
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome.
authors.forename: Luca
authors.initials: L
authors.lastname: Carioti
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome.
authors.forename: Michela
authors.initials: M
authors.lastname: Pollicita
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome.
authors.forename: Romina
authors.initials: R
authors.lastname: Salpini
authors.affiliation: Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Caserta.
authors.forename: Evangelista
authors.initials: E
authors.lastname: Sagnelli
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome.
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
authors.affiliation: Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Caserta.
authors.forename: Nicola
authors.initials: N
authors.lastname: Coppola
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome.
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
mesh_terms: D000208:Acute Disease; D000328:Adult; D019943:Amino Acid Substitution; D015331:Cohort Studies; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006509:Hepatitis B / Q000453:epidemiology / Q000276:immunology / Q000821:virology*; D006514:Hepatitis B Surface Antigens / Q000235:genetics* / Q000276:immunology; D006515:Hepatitis B virus / Q000145:classification / Q000235:genetics* / Q000276:immunology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D006514:Hepatitis B Surface Antigens; D012194:RNA-Directed DNA Polymerase
keywords: HBV; HBsAg; acute infection; quasispecies; reverse transcriptase