Overlapping structure of hepatitis B virus (HBV) genome and immune selection pressure are critical forces modulating HBV evolution.
How the overlap between the hepatitis B virus (HBV) reverse transcriptase (RT) and HBV S antigen (HBsAg) genes modulates the extent of HBV genetic variability is still an open question, and was investigated here. The rate of nucleotide conservation (≤1% variability) followed an atypical pattern in the RT gene, due to an overlap between RT and HBsAg (69.9% nucleotide conservation in the overlapping region vs 41.2% in the non-overlapping region; P<0.001), with a consequently lower rate of synonymous substitution within the overlapping region [median(interquartile range)dS=3.1(1.5-7.4) vs 20.1(10.6-30.0); P=3.249×10(-22)]. The most conserved RT regions were located within the YMDD motif and the N-terminal parts of the palm and finger domains, critical for RT functionality. These regions also corresponded to highly conserved HBsAg domains that are critical for HBsAg secretion. Conversely, the genomic region encoding the HBsAg antigenic loop (where immune-escape mutations are localized) showed a sharp decrease in the extent of conservation (40.6%), which was less pronounced in the setting of human immunodeficiency virus (HIV)-driven immune suppression (48.8% in HIV-HBV co-infection vs 21.5% in mono-infected patients; P=0.020). In conclusion, the overlapping reading frame and the immune system appear to have shaped the patterns of RT and HBsAg genetic variability. Highly conserved regions in RT and HBsAg may deserve further attention as novel therapeutic targets.
Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome 00133, Italy.
Valeria
V
Cento
Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome 00133, Italy.
Carmen
C
Mirabelli
Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome 00133, Italy.
Salvatore
S
Dimonte
Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome 00133, Italy.
Romina
R
Salpini
Department of Infectious Diseases, Rui Jin Hospital, Shanghai Jiao Tong University, Shanghai 200025, PR China.
Yue
Y
Han
Bordeaux University Hospital, University Victor Segalen, Bordeaux 33076, France.
Pascale
P
Trimoulet
University Hospital 'Tor Vergata', Rome 00133, Italy.
Ada
A
Bertoli
'L. Sacco' Hospital, Milan 20157, Italy.
Valeria
V
Micheli
'L. Sacco' Hospital, Milan 20157, Italy.
Guido
G
Gubertini
'S. Pertini' Hospital, Rome 00157, Italy.
Giuseppina
G
Cappiello
'S. Pertini' Hospital, Rome 00157, Italy.
Alberto
A
Spanò
'S. Pertini' Hospital, Rome 00157, Italy.
Roberta
R
Longo
'S. Pertini' Hospital, Rome 00157, Italy.
Martina
M
Bernassola
Hospital 'Santa Maria Annunziata', Florence 50126, Italy.
Francesco
F
Mazzotta
University 'La Sapienza', Rome 00185, Italy.
Giuseppe Maria
GM
De Sanctis
Department of Infectious Diseases, Rui Jin Hospital, Shanghai Jiao Tong University, Shanghai 200025, PR China.
Xin Xin
XX
Zhang
University of Cologne, Cologne 50923, Germany.
Jens
J
Verheyen
Infectious Diseases Unit, University of Milan, Milan 20122, Italy.
Antonella
A
D'Arminio Monforte
Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome 00133, Italy.
Francesca
F
Ceccherini-Silberstein
Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome 00133, Italy.
Carlo Federico
CF
Perno
Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome 00133, Italy.
Valentina
V
Svicher
D000595:Amino Acid Sequence; D001483:Base Sequence; D060085:Coinfection / Q000235:genetics / Q000276:immunology; D019143:Evolution, Molecular; D014644:Genetic Variation; D016679:Genome, Viral; D006678:HIV / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000276:immunology; D006515:Hepatitis B virus / Q000235:genetics* / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000276:immunology
D006514:Hepatitis B Surface Antigens; D012194:RNA-Directed DNA Polymerase