Viruses (Jul 2018)

HDV Can Constrain HBV Genetic Evolution in HBsAg: Implications for the Identification of Innovative Pharmacological Targets

  • Luna Colagrossi,
  • Romina Salpini,
  • Rossana Scutari,
  • Luca Carioti,
  • Arianna Battisti,
  • Lorenzo Piermatteo,
  • Ada Bertoli,
  • Lavinia Fabeni,
  • Carmine Minichini,
  • Pascale Trimoulet,
  • Hervé Fleury,
  • Elena Nebuloso,
  • Maria De Cristofaro,
  • Giuseppina Cappiello,
  • Alberto Spanò,
  • Vincenzo Malagnino,
  • Terenzio Mari,
  • Angelo Barlattani,
  • Nerio Iapadre,
  • Miriam Lichtner,
  • Claudio Mastroianni,
  • Ilaria Lenci,
  • Caterina Pasquazzi,
  • Giuseppe Maria De Sanctis,
  • Alfonso Galeota Lanza,
  • Maria Stanzione,
  • Gianfranca Stornaiuolo,
  • Massimo Marignani,
  • Loredana Sarmati,
  • Massimo Andreoni,
  • Mario Angelico,
  • Francesca Ceccherini-Silberstein,
  • Carlo-Federico Perno,
  • Nicola Coppola,
  • Valentina Svicher

DOI
https://doi.org/10.3390/v10070363
Journal volume & issue
Vol. 10, no. 7
p. 363

Abstract

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Chronic HBV + HDV infection is associated with greater risk of liver fibrosis, earlier hepatic decompensation, and liver cirrhosis hepatocellular carcinoma compared to HBV mono-infection. However, to-date no direct anti-HDV drugs are available in clinical practice. Here, we identified conserved and variable regions in HBsAg and HDAg domains in HBV + HDV infection, a critical finding for the design of innovative therapeutic agents. The extent of amino-acid variability was measured by Shannon-Entropy (Sn) in HBsAg genotype-d sequences from 31 HBV + HDV infected and 62 HBV mono-infected patients (comparable for demographics and virological-parameters), and in 47 HDAg genotype-1 sequences. Positions with Sn = 0 were defined as conserved. The percentage of conserved HBsAg-positions was significantly higher in HBV + HDV infection than HBV mono-infection (p = 0.001). Results were confirmed after stratification for HBeAg-status and patients’ age. A Sn = 0 at specific positions in the C-terminus HBsAg were correlated with higher HDV-RNA, suggesting that conservation of these positions can preserve HDV-fitness. Conversely, HDAg was characterized by a lower percentage of conserved-residues than HBsAg (p < 0.001), indicating higher functional plasticity. Furthermore, specific HDAg-mutations were significantly correlated with higher HDV-RNA, suggesting a role in conferring HDV replicative-advantage. Among HDAg-domains, only the virus-assembly signal exhibited a high genetic conservation (75% of conserved-residues). In conclusion, HDV can constrain HBsAg genetic evolution to preserve its fitness. The identification of conserved regions in HDAg poses the basis for designing innovative targets against HDV-infection.

Keywords