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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)dS53.1(1.5-7.4) vs 20.1(10.6-30.0); P53.249¾10"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 coinfection vs 21.5 % in mono-infected patients; P50.020). 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.About 2 billion people worldwide are infected with hepatitis B virus (HBV), and about 350 million presently live with chronic HBV infection (WHO, 2012), thus making this viral infection a global health concern.3On behalf of the ICoNA study group.

This study shows a high prevalence of viruses in the lower respiratory tract samples of hospitalized adults, mostly HRV and FLU-A. It is not possible to establish the role of viruses detected at low frequency, but our findings suggest the necessity to consider them as potential causes or precursors of lower respiratory tract infections (LRTIs).