Background Given the high mortality rate for those with end-stage kidney d sease on dialysis and the efficacy and safety of current hepatitis C virus (HCV) treatments, currently-discarded kidneys from HCV-infected (HCV+) donors may be a neglected public health resource. Objective To determine the tolerability and feasibility of kidney transplantation (KT) from HCV+ donors to HCV-uninfected recipients (HCV D+/R−) in combination with direct-acting antivirals (DAAs) as pre- and post-transplant prophylaxis. Design Open-label, non-randomized trial. (ClinicalTrials.gov: NCT02781649) Setting Single-center. Participants 10 HCV-uninfected KT candidates over the age of 50 years with no available living donors. Intervention KT from deceased donors ages 13–50 years with a positive HCV RNA and HCV antibody test. All recipients received a dose of grazoprevir 100 mg/elbasvir 50 mg (GZR/EBR) immediately prior to transplant. For genotype 1 donors, recipients continued GZR/EBR for 12 weeks post-transplant; for genotype 2 or 3 donors, sofosbuvir 400 mg was added to GZR/EBR for 12 weeks of triple-therapy. Measurements The primary safety outcome was the incidence of adverse events related to GZR-EBR. The primary efficacy outcome was the proportion recipients with HCV RNA less than the lower limit of quantification 12 weeks after prophylaxis. Results Among 10 HCV D+/R− there were no treatment-related adverse events and HCV RNA was not detected in any recipient 12 weeks after treatment. Limitations Nonrandomized study design and small number of patients. Conclusions Pre- and post-transplant HCV treatment was safe and prevented chronic hepatitis C in HCV D+/R− KT. If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for HCV− KT candidates.

No abstract

Cyclic-G/AMP (cGAMP) synthase (cGAS) triggers host innate immune responses against cytosolic double-stranded (ds)DNA arising from genotoxic stress and pathogen invasion. The canonical activation mechanism of cGAS entails dsDNA-binding and dimerization. Here, we report an unexpected activation mechanism of cGAS in which Mn2+ activates monomeric cGAS without dsDNA. Importantly, the Mn2+-mediated activation positively couples with dsDNA-dependent activation in a concerted manner. Moreover, the positive coupling between Mn2+ and dsDNA length-dependent activation requires the cognate ATP/GTP substrate pair, while negative-cooperativity suppresses Mn2+ utilization by either ATP or GTP alone. Additionally, while Mn2+ accelerates the overall catalytic activity, dsDNA length-dependent dimerization specifically accelerates the cyclization of cGAMP. Together, we demonstrate how the intrinsic allostery of cGAS efficiently yet precisely tunes its activity.

No abstract