RT Journal Article SR Electronic(1) A1 Cento, Valeria A1 Mirabelli, Carmen A1 Dimonte, Salvatore A1 Salpini, Romina A1 Han, Yue A1 Trimoulet, Pascale A1 Bertoli, Ada A1 Micheli, Valeria A1 Gubertini, Guido A1 Cappiello, Giuseppina A1 Spanò, Alberto A1 Longo, Roberta A1 Bernassola, Martina A1 Mazzotta, Francesco A1 De Sanctis, Giuseppe Maria A1 Zhang, Xin Xin A1 Verheyen, Jens A1 D’Arminio Monforte, Antonella A1 Ceccherini-Silberstein, Francesca A1 Perno, Carlo Federico A1 Svicher, ValentinaYR 2013 T1 Overlapping structure of hepatitis B virus (HBV) genome and immune selection pressure are critical forces modulating HBV evolution JF Journal of General Virology, VO 94 IS 1 SP 143 OP 149 DO https://doi.org/10.1099/vir.0.046524-0 PB Microbiology Society, SN 1465-2099, AB 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., UL https://www.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.046524-0