Maxwell Robidoux

OBJECTIVE: Chronic HBV infection affects more than 250 million people worldwide and remains a global healthcare problem in part because we lack curative treatment. Sustained viral control requires HBV-specific T cells, but these become functionally impaired in chronic infection. Clinical evidence indicates that functional cure of HBV infection by the host immune response is feasible. Developing T cell-based therapies able to achieve functional cure will require identification of the requirements for a successful T cell response against HBV and the relative contribution of individual T cell specificities to HBV control. DESIGN: The phenotype and function of HBV-specific T cells were studied directly ex vivo using fluorochrome-labelled multimers. We studied multiple HBV-specific T cell specificities targeting different HBV proteins in individuals with either an acute self-limiting or chronic HBV infection. RESULTS: We detected strong T cell responses targeting multiple HBV viral proteins in acute self-limiting and low-frequency core and polymerase-specific T cells in chronic infection. Expression of the T cell inhibitory receptor PD-1, as well as T cell differentiation, T cell function and T cell regulation differed by stages and outcomes of infection. In addition, these features differed significantly between T cells targeting different HBV specificities. CONCLUSION: HBV-specific T cells with different target specificities are characterised by distinct phenotypical and functional profiles. These results have direct implications for the design of immunological studies in HBV infection, and are potentially relevant for informing immunotherapeutic approaches to induce functional cure.

Summary The role of the endogenous interferon ( IFN ) system has been well characterized during IFN ‐based therapy for chronic hepatitis C virus ( HCV ) infection; less is known for direct‐acting antivirals ( DAA s). In this phase 3b open‐label study, we assessed changes in IFN ‐stimulated genes ( ISG s) in non‐cirrhotic treatment‐naïve or peg IFN / RBV ‐experienced HCV ‐ GT 1a‐infected patients receiving paritaprevir/ritonavir/ombitasvir + dasabuvir + ribavirin (Pr OD + R) for 12 weeks. ISG expression was quantified from peripheral blood mononuclear cells at baseline, treatment weeks ( TW )2, TW 4, TW 8, end of treatment ( EOT ) and at post‐treatment week 12. Paired sera were used to assess IFN ‐α/ IFN ‐related chemokines/cytokines. Twenty‐five patients were enrolled. Overall sustained virologic response ( SVR )12 was 92% (no virologic failure [ VF ]) and 100% for those completing the study protocol. Two patients were excluded from the ISG analysis due to lack of post‐treatment samples. The majority of ISG s were downregulated at TW 2‐ TW 4 (nadir TW 4); however, a relative increase was observed at TW 8‐ EOT , although levels were lower than baseline. This downregulation was accompanied by increases in IFN ‐α/ IFN ‐related chemokines, a finding not observed with T H 1/2‐related cytokines. Following SVR , ISG expression returned to TW 2 levels. In conclusion, Pr OD + R for 12 weeks was well‐tolerated with no VF . Our data demonstrate dynamic alterations in innate immune profiles during highly potent IFN ‐free DAA therapy. The downregulation of ISG post‐therapy suggests reversal of the “exhausted” ISG phenotype following SVR , and the rise in ISG s and IFN ‐α/ IFN ‐responsive chemokines late during therapy suggests resetting of IFN responsiveness that may be relevant in determining duration of or immunological sequelae from DAA therapy, including HBV reactivation.

Mentholated cigarettes capture a quarter of the US market, and are disproportionately smoked by adolescents. Menthol allosterically modulates nicotinic acetylcholine receptor function, but its effects on the brain and nicotine addiction are unclear. To determine if menthol is psychoactive, we assessed locomotor sensitization and brain functional connectivity. Adolescent male Sprague Dawley rats were administered nicotine (0.4 mg/kg) daily with or without menthol (0.05 mg/kg or 5.38 mg/kg) for nine days. Following each injection, distance traveled in an open field was recorded. One day after the sensitization experiment, functional connectivity was assessed in awake animals before and after drug administration using magnetic resonance imaging. Menthol (5.38 mg/kg) augmented nicotine-induced locomotor sensitization. Functional connectivity was compared in animals that had received nicotine with or without the 5.38 mg/kg dosage of menthol. Twenty-four hours into withdrawal after the last drug administration, increased functional connectivity was observed for ventral tegmental area and retrosplenial cortex with nicotine+menthol compared to nicotine-only exposure. Upon drug re-administration, the nicotine-only, but not the menthol groups, exhibited altered functional connectivity of the dorsal striatum with the amygdala. Menthol, when administered with nicotine, showed evidence of psychoactive properties by affecting brain activity and behavior compared to nicotine administration alone.