HBV DNA integration: Molecular mechanisms and clinical implications

© 2017 by the authors. Chronic infection with the Hepatitis B Virus (HBV) is amajor cause of liver-related morbidity and mortality. One peculiar observation in cells infected with HBV (or with closely-related animal hepadnaviruses) is the presence of viral DNA integration in the host cell genome, despite this form being a replicative dead-end for the virus. The frequent finding of somatic integration of viral DNA suggests an evolutionary benefit for the virus; however, the mechanism of integration, its functions, and the clinical implications remain unknown. Here we review the current body of knowledge of HBV DNA integration, with particular focus on the molecular mechanisms and its clinical implications (including the possible consequences of replication-independent antigen expression and its possible role in hepatocellular carcinoma). HBV DNA integration is likely to influence HBV replication, persistence, and pathogenesis, and so deserves greater attention in future studies

Medullary serotonergic neurones and adjacent neurones that express neurokinin-1 receptors are both involved in chemoreception in vivo

Neurokinin-1 receptor (NK1R)-expressing neurones that are involved in chemoreception at the retrotrapezoid nucleus (Nattie & Li, 2002b) are also prominent at locations that contain medullary serotonergic neurones, which are chemosensitive in vitro. In medullary regions containing both types, we evaluated their role in central chemoreception by specific cell killing. We injected (2×100 nl) (a) substance P–saporin (SP-SAP; 1μm) to kill NK1R-expressing neurones, (b) a novel conjugate of a monoclonal antibody to the serotonin transporter (SERT) and saporin (anti-SERT-SAP; 1μm) to kill serotonergic neurones, or (c) SP-SAP and anti-SERT-SAP together to kill both types. Controls received IgG-SAP injections (1μm). There was no double-labelling of NK1R-immunoreactive (ir) and tryptophan-hydroxylase (TPOH)-ir neurones. Cell (somatic profile) counts showed that NK1R-ir neurones in the SP-SAP group were reduced by 31%; TPOH-ir neurones in the anti-SERT-SAP group by 28%; and NK1R-ir and TPOH-ir neurones, respectively, in the combined lesion group by 55% and 31% (P < 0.001; two-way ANOVA; P < 0.05, Tukey's post hoc test). The treatments had no significant effect on sleep/wake time, body temperature, or oxygen consumption but all three reduced the ventilatory response to 7% inspired CO(2) in wakefulness and sleep by a similar amount. SP-SAP treatment decreased the averaged CO(2) responses (3, 7 and 14 days after lesions) in wakefulness and sleep by 21% and 16%, anti-SERT-SAP decreased the responses by 15% and 18%, and the combined treatment decreased the responses by 12% and 12% (P < 0.001; two-way ANOVA; P < 0.05, Tukey's post hoc test). We conclude that separate populations of serotonergic and adjacent NK1R-expressing neurones in the medulla are both involved in central chemoreception in vivo