Imprinted immune abnormalities in liver transplant patients cured of hepatitis C with antiviral drugs

Chronic hepatitis C virus (HCV) infection induces interferon and dysregulates immune responses through inflammation and chronic antigenic stimulation. Antiviral drugs can cure HCV, providing a unique opportunity to examine the immunological restoration that does and does not occur when a chronic viral infection is eradicated. We quantified blood cytokines levels and used mass cytometry to immunophenotype peripheral blood mononuclear cells (PBMCs) before and after HCV cure in two groups of patients and controls. At baseline, serum IFN alpha and sCD163 (a macrophage product) were elevated in both liver transplant and non-liver transplant patients compared to controls; the frequencies of several PBMC populations differed from controls; and PD- positivity was increased in nearly all T cell subsets. Many abnormalities persisted after HCV cure, including elevated PD-1 expression on CD4 naive and central memory T cells, elevated sCD163, and expansion of the plasmablast/plasma cell compartment. Several myeloid lineage subsets, including antigen presenting dendritic cells, remained dysregulated. In mechanistic studies, IFN alpha treatment increased PD-1 on human T cells and increased T cell receptor signaling. The data identify immunological abnormalities that persist after curative HCV treatment. Prior to cure, high levels of IFN alpha may stimulate PD-1 expression on human T cells, causing persistent functional changes.