Intact Dendritic Cell Pathogen-Recognition Receptor Functions Associate with Chronic Hepatitis C Treatment-Induced Viral Clearance

Abstract

Although studies have addressed the exhaustion of the host's immune response to HCV and its role in treatment, there is little information about the possible contribution of innate immunity to treatment-induced clearance. We hypothesized that because intact myeloid dendritic cell (MDC) pathogen sensing functions are associated with improved HCV-specific CD8+ T cell functionality in some chronically infected patients, it might enhance HCV clearance rate under standard interferon therapy. To investigate this hypothesis, TLR-induced MDC activation and HCV-specific CD8+ T cell response quality were monitored longitudinally at the single-cell level using polychromatic flow cytometry in chronically infected patients undergoing interferon therapy. We correlated the immunological, biochemical and virological data with response to treatment. We demonstrate that the clinical efficacy of interferon-induced viral clearance is influenced by the extent to which HCV inhibits MDC functions before treatment, rather than solely on a breakdown of the extrinsic T cell immunosuppressive environment. Thus, viral inhibition of MDC functions before treatment emerges as a co-determining factor in the clinical efficacy of interferon therapy during chronic HCV infection.

Acute Liver Damage Associated with Innate Immune Activation in a Small Nonhuman Primate Model of Hepacivirus Infection

“…Maintenance of normal dendritic cell (DC) phenotypes and functional repertoires has been shown to be critical for sustained antiviral responses and is necessary to augment antiviral therapies, including alpha interferon (IFN-␣), which can block GBV-B infection in vitro (27)(28)(29). Conversely, GBV-B has evolved to inhibit IFN-␣ production, and HCV has similarly developed mechanisms to subvert plasmacytoid (pDCs) and myeloid (mDCs) DCs, decreasing the levels of IFN-␣, interleukin-10 (IL-10), and IL-12 (30)(31)(32), all of which are necessary for initiation of T cell responses and mobilization of natural killer (NK) cells.…”