An effective interferon-gamma-mediated inhibition of hepatitis C virus replication by natural killer cells is associated with spontaneous clearance of acute hepatitis C in human immunodeficiency virus-positive patients

Kokordelis, P; Krämer, Benjamin; Körner, Christian; Boesecke, Christoph; Voigt, Esther; Ingiliz, Patrick; Glässner, A; Eisenhardt, M; Wolter, F; Kaczmarek, Dominik J.; Nischalke, Hans Dieter; Rockstroh, Jürgen K.; Spengler, Ulrich; Nattermann, Jacob

doi:10.1002/hep.26782

Cited by 52 publications

(46 citation statements)

References 37 publications

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“…These features persisted in the postacute period, but most functions resolved to baseline levels by the time of virus clearance. Empirical HCV studies suggest that enhanced NK cell function during acute infection can lead to viral containment (46)(47)(48), and in persons accidentally exposed to HCV, NK cells exert upregulated effector functions (36). Collectively, these data may suggest that the robust NK cell response we observed in acute GBV-B infection is related to the virus clearance normally observed (40,49).…”

Section: Discussionmentioning

confidence: 63%

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

Manickam

Rajakumar

Wachtman

et al. 2016

J Virol

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Despite its importance in shaping adaptive immune responses, viral clearance, and immune-based inflammation, tissue-specific innate immunity remains poorly characterized for hepatitis C virus (HCV) infection due to the lack of access to acutely infected tissues. In this study, we evaluated the impact of natural killer (NK) cells and myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells on control of virus replication and virus-induced pathology caused by another, more rapidly resolving hepacivirus, GB virus B (GBV-B), in infections of common marmosets. High plasma and liver viral loads and robust hepatitis characterized acute GBV-B infection, and while viremia was generally cleared by 2 to 3 months postinfection, hepatitis and liver fibrosis persisted after clearance. Coinciding with peak viral loads and liver pathology, the levels of NK cells, mDCs, and pDCs in the liver increased up to 3-fold. Although no obvious numerical changes in peripheral innate cells occurred, circulating NK cells exhibited increased perforin and Ki67 expression levels and increased surface expression of CXCR3. These data suggested that increased NK cell arming and proliferation as well as tissue trafficking may be associated with influx into the liver during acute infection. Indeed, NK cell frequencies in the liver positively correlated with plasma (R ‫؍‬ 0.698; P ‫؍‬ 0.015) and liver (R ‫؍‬ 0.567; P ‫؍‬ 0.057) viral loads. Finally, soluble factors associated with NK cells and DCs, including gamma interferon (IFN-␥) and RANTES, were increased in acute infection and also were associated with viral loads and hepatitis. Collectively, the findings showed that mobilization of local and circulating innate immune responses was linked to acute virus-induced hepatitis, and potentially to resolution of GBV-B infection, and our results may provide insight into similar mechanisms in HCV infection. IMPORTANCEHepatitis C virus (HCV) infection has created a global health crisis, and despite new effective antivirals, it is still a leading cause of liver disease and death worldwide. Recent evidence suggests that innate immunity may be a potential therapeutic target for HCV, but it may also be a correlate of increased disease. Due to a lack of access to human tissues with acute HCV infection, in this study we evaluated the role of innate immunity in resolving infection with a hepacivirus, GBV-B, in common marmosets. Collectively, our data suggest that NK cell and DC mobilization in acute hepacivirus infection can dampen virus replication but also regulate acute and chronic liver damage. How these two opposing effects on the host may be modulated in future therapeutic and vaccine approaches warrants further study. H epatitis C virus (HCV) infection has become a global health epidemic, with the virus infecting more than 170 million people worldwide (1) and resulting in 350,000 HCV-related liver disease deaths each year (2). HCV infection results in the following two disparate manifestations: (i) an acute, self-resolving infection and (ii) a chron...

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Section: Discussionmentioning

confidence: 63%

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

Manickam

Rajakumar

Wachtman

et al. 2016

J Virol

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“…In these cases, protected individuals had an increased frequency of NK cells, as well as increased IFNγ production and cytotoxicity. In co-culture experiments, it was shown that NK cells inhibit HCV replication by secreting IFNγ 55,56 . In particular, NKp46 high NK cells efficiently suppressed HCV replication 57,58 .…”

Section: Natural Killer Cellsmentioning

confidence: 98%

“…Chronic exposure to type I IFNs increases STAT1 expression in NK cells, which results in STAT1 dominance over STAT4 in intracellular signalling pathways 62,63 . As a consequence, NK cells upregulate expression of the apoptosis-inducing ligand TRAIL (also known as TNFSF10) and have increased cyto toxicity, whereas they have decreased IFNγ production 62,63 , which is an important effector function of NK cells for HCV control 56 .…”

Section: Natural Killer Cellsmentioning

confidence: 99%

Immune responses and immunopathology in acute and chronic viral hepatitis

2016

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Hepatitis A virus (HAV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are responsible for most cases of viral hepatitis. Infection by each type of virus results in a different typical natural disease course and clinical outcome that are determined by virological and immunological factors. HCV tends to establish a chronic persistent infection, whereas HAV does not. HBV is effectively controlled in adults, although it persists for a lifetime after neonatal infection. In this Review, we discuss the similarities and differences in immune responses to and immunopathogenesis of HAV, HBV and HCV infections, which may explain the distinct courses and outcomes of each hepatitis virus infection.

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“…While the exact mechanisms underlying these distinct immune activation profiles are not well understood, previous studies have suggested some crucial roles of these genes, such as the elevation of CX3CL1 as a marker of liver fibrosis/injury [29], TGF-β as a potent inducer of fibrogenesis [26], and interferon-α inhibiting HCV replication [42]. Interestingly, a recent study has reported that an effective interferon-γ mediated inhibition of HCV replication by NK cells is associated with spontaneous clearance of HCV in HIV+ patients [43], which is in line with our simultaneous detections of both the dysregulation of NK cytotoxicity pathway and the decreased expression of IFNG in co-infected individuals.…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono and co-infection identified by transcriptome profiling of PBMCs

Wu¹

2015

Health Care: Current Reviews

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Background: Despite the easy accessibility and diagnostic utility of PBMCs and their potential to show distinct expression patterns associated with the accelerated disease progression in HIV/HCV co-infection, there has not been a systematic study focusing on the global dysregulations of the biological pathways in PBMCs from HIV, HCV mono-and co-infected individuals. This study aimed at identifying the transcriptome distinctions of PBMCs between these patient groups. Methods: Genome-wide transcriptomes of PBMCs from 10 HIV/HCV co-infected patients, 7 HIV+ patients, 5 HCV+ patients, and 5 HIV/HCV sero-negative healthy controls were analyzed using Illumina microarray. Pairwise comparisons were performed to identify differentially expressed genes (DEGs), followed by gene set enrichment analysis (GSEA) to detect the global dysregulations of the biological pathways between HIV, HCV mono-and co-infection.

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An effective interferon-gamma-mediated inhibition of hepatitis C virus replication by natural killer cells is associated with spontaneous clearance of acute hepatitis C in human immunodeficiency virus-positive patients

Cited by 52 publications

References 37 publications

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

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

Immune responses and immunopathology in acute and chronic viral hepatitis

Differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono and co-infection identified by transcriptome profiling of PBMCs

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