Journal Article

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

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

2018

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Adult / Amino acids / Antigens / Antiviral Agents - pharmacology / C-Terminus / Chronic infection / Cirrhosis / Coinfection / Conservation / Demography / Deoxyribonucleic acid / DNA / Drug development / Evolution & development / Evolution, Molecular / Female / Fibrosis / Functional plasticity / Genetic Variation / Genomes / Genotype / Genotype & phenotype / Genotypes / HBsAg / HDAg / HDV-RNA / Hepatitis / Hepatitis B - diagnosis / Hepatitis B - virology / Hepatitis B e antigen / Hepatitis B surface antigen / Hepatitis B Surface Antigens - chemistry / Hepatitis B Surface Antigens - genetics / Hepatitis B virus - drug effects / Hepatitis B virus - genetics / Hepatitis delta virus / Hepatitis Delta Virus - physiology / Hepatocellular carcinoma / Hepatology / Hospitals / Humans / Infections / Infectious diseases / Liver cancer / Liver cirrhosis / Male / Medical innovations / Microbial Interactions / Middle Aged / Models, Molecular / Mutation / Patients / Pertini, Alessandro (1896-1990) / Phylogeny / Protein Conformation / Reproductive fitness / Ribonucleic acid / RNA / RNA polymerase / RNA, Viral / Stratification / Viral Proteins - chemistry / Viral Proteins - genetics / Viral Proteins - metabolism