The liver bears unique immune properties that support both immune tolerance and immunity, but the mechanisms responsible for clearance versus persistence of virus-infected hepatocytes remain unclear. Here, we dissect the factors determining the outcome of antiviral immunity using recombinant adenoviruses that reflect the hepatropism and hepatrophism of hepatitis viruses. We generated replication-deficient adenoviruses with equimolar expression of ovalbumin, luciferase, and green fluorescent protein driven by a strong ubiquitous cytomegalovirus (CMV) promoter (Ad-CMV-GOL) or by 100-fold weaker, yet hepatocyte-specific, transthyretin (TTR) promoter (Ad-TTR-GOL). Using in vivo bioluminescence to quantitatively and dynamically image luciferase activity, we demonstrated that Ad-TTR-GOL infection always persists, whereas Ad-CMV-GOL infection is always cleared, independent of the number of infected hepatocytes. Failure to clear Ad-TTR-GOL infection involved mechanisms acting during initiation as well as execution of antigen-specific immunity. First, hepatocyte-restricted antigen expression led to delayed and curtailed T-cell expansion-10,000-fold after Ad-CMV-GOL versus 150-fold after Ad-TTR-GOL-infection. Second, CD8 T-cells primed toward antigens selectively expressed by hepatocytes showed high PD-1/Tim-3/LAG-3/CTLA-4/CD160 expression levels similar to that seen in chronic hepatitis B. Third, Ad-TTR-GOL but not Ad-CMV-GOL-infected hepatocytes escaped being killed by effector T-cells while still inducing high PD-1/Tim-3/LAG-3/CTLA-4/CD160 expression, indicating different thresholds of T-cell receptor signaling relevant for triggering effector functions compared with exhaustion. Conclusion: Our study identifies deficits in the generation of CD8 T-cell immunity toward hepatocyte-expressed antigens and escape of infected hepatocytes expressing low viral antigen levels from effector T-cell killing as independent factors promoting viral persistence. This highlights the importance of addressing both the restauration of CD8 T-cell dysfunction and overcoming local hurdles of effector T-cell function to eliminate virus-infected hepatocytes.

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BackgroundNV infections in immunocompromised patients could cause chronic gastroenteritis (GE) with devastating consequences. A successful reduction of the medical immunsuppression in patients with NV GE and SOT have been reported repeatedly, but the optimal approach in these patients is less well defined.MethodsWe identified patients with PCR-confirmed NV GE and SOT from a laboratory database and patients with other underlying conditions from a clinical database. Clinical data were retrieved from pt files and by telephone interviews. The severity of GE was assessed by the Vesikari score (VS). Subgroups were dichotomised at their medians. Continuous variables were compared by Kruskal–Wallis test and time-dependant variables were compared by Kaplan–Meier analyses and log-rank test.ResultsOverall, 101 patients (age: 1–90 years, median 60) with SOT (36), hematopoietic stem cell transplantation (HSCT, 23), hematological malignancies (HM, 20), solid tumor (ST, 8), and other nonimmunocompromising conditions (14) were identified. Patients with SOT had received kidney (30), combined kidney/pancreas (4), liver/pancreas/stomach/small bowel (1), or liver/small bowel (1) transplantation.The median duration of symptoms was significantly longer in patients with SOT compared with those with other conditions (SOT 26, HSCT 12, HM 5, ST 4, other 3 days; Figure 1, P < 0.0001), but the disease severity (VS, 74 patients with sufficient data; Figure 2) was not significantly different across the risk groups.Age, time since transplantation, the use of calcineurin inhibitors vs. other drugs for immunosuppression, and comparison of kidney only vs. other organ transplantation were not predictive for a prolonged duration of NV GE in SOT patients. Interestingly, a reduction of the immunosuppression (IS) in SOT patients (dose reduction or drug termination) was associated with a prolonged duration of symptoms (median 47 vs. 14 days; Figure 3, P = 0.0007). ConclusionIn this series of patients, SOT was associated with a prolonged duration of NV GE. A reduction of the immunosuppression was associated with a prolonged disease duration in SOT patients. It remains unclear whether this observation is due to a selection bias, or aggravation of symptoms were caused by immune reconstitution with reduced immunosuppressive therapy.Disclosures All authors: No reported disclosures.