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β-Dystrobrevin, a member of the dystrobrevin protein family, is a dystrophin-related and -associated protein restricted to non-muscle tissues and is highly expressed in kidney, liver and brain. Dystrobrevins are now thought to play an important role in intracellular signal transduction, in addition to providing a membrane scaffold in muscle, but the precise role of β-dystrobrevin has not yet been determined. To study β-dystrobrevin's function in brain, we used the yeast two-hybrid approach to look for interacting proteins. Four overlapping clones were identified that encoded Kif5A, a neuronal member of the Kif5 family of proteins that consists of the heavy chains of conventional kinesin. A direct interaction of β-dystrobrevin with Kif5A was confirmed by in vitro and in vivo association assays. Co-immunoprecipitation with a monoclonal kinesin heavy chain antibody precipitated both α- and β-dystrobrevin, indicating that this interaction is not restricted to the β-dystrobrevin isoform. The site for Kif5A binding to β-dystrobrevin was localized in a carboxyl-terminal region that seems to be important in heavy chain-mediated kinesin interactions and is highly homologous in all three Kif5 isoforms, Kif5A, Kif5B and Kif5C. Pull-down and immunofluorescence experiments also showed a direct interaction between β-dystrobrevin and Kif5B. Our findings suggest a novel function for dystrobrevin as a motor protein receptor that might play a major role in the transport of components of the dystrophin-associated protein complex to specific sites in the cell.

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.

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