@article{mbs:/content/journal/jgv/10.1099/vir.0.046524-0, author = "Cento, Valeria and Mirabelli, Carmen and Dimonte, Salvatore and Salpini, Romina and Han, Yue and Trimoulet, Pascale and Bertoli, Ada and Micheli, Valeria and Gubertini, Guido and Cappiello, Giuseppina and Spanò, Alberto and Longo, Roberta and Bernassola, Martina and Mazzotta, Francesco and De Sanctis, Giuseppe Maria and Zhang, Xin Xin and Verheyen, Jens and D’Arminio Monforte, Antonella and Ceccherini-Silberstein, Francesca and Perno, Carlo Federico and Svicher, Valentina", title = "Overlapping structure of hepatitis B virus (HBV) genome and immune selection pressure are critical forces modulating HBV evolution", journal= "Journal of General Virology", year = "2013", volume = "94", number = "1", pages = "143-149", doi = "https://doi.org/10.1099/vir.0.046524-0", url = "https://www.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.046524-0", publisher = "Microbiology Society", issn = "1465-2099", type = "Journal Article", abstract = "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.", }