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.

Colagrossi, L., Salpini, R., Scutari, R., Carioti, L., Battisti, A., Piermatteo, L., et al. (2018). HDV can constrain HBV genetic evolution in hbsag: Implications for the identification of innovative pharmacological targets. VIRUSES, 10(7), 363 [10.3390/v10070363].

HDV can constrain HBV genetic evolution in hbsag: Implications for the identification of innovative pharmacological targets

Colagrossi L.;Salpini R.;Scutari R.;Piermatteo L.;Malagnino V.;Mastroianni C.;Lenci I.;Sarmati L.;Andreoni M.;Angelico M.;Ceccherini-Silberstein F.;Svicher V.
2018-07-09

Abstract

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.
9-lug-2018
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/17 - MALATTIE INFETTIVE
English
Con Impact Factor ISI
HBsAg; HDAg; HDV-RNA; Adult; Antiviral Agents; Coinfection; Female; Genetic Variation; Genotype; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis Delta Virus; Humans; Male; Middle Aged; Models, Molecular; Mutation; Phylogeny; Protein Conformation; RNA, Viral; Viral Proteins; Evolution, Molecular; Microbial Interactions
Colagrossi, L., Salpini, R., Scutari, R., Carioti, L., Battisti, A., Piermatteo, L., et al. (2018). HDV can constrain HBV genetic evolution in hbsag: Implications for the identification of innovative pharmacological targets. VIRUSES, 10(7), 363 [10.3390/v10070363].
Colagrossi, L; Salpini, R; Scutari, R; Carioti, L; Battisti, A; Piermatteo, L; Bertoli, A; Fabeni, L; Minichini, C; Trimoulet, P; Fleury, H; Nebuloso, E; De Cristofaro, M; Cappiello, G; Spano, A; Malagnino, V; Mari, T; Barlattani, A; Iapadre, N; Lichtner, M; Mastroianni, C; Lenci, I; Pasquazzi, C; De Sanctis, Gm; Lanza, Ag; Stanzione, M; Stornaiuolo, G; Marignani, M; Sarmati, L; Andreoni, M; Angelico, M; Ceccherini-Silberstein, F; Perno, C-; Coppola, N; Svicher, V
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/204641
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