Analysis of Successful Immune Responses in Persons Infected with Hepatitis C Virus

Although hepatitis C virus (HCV) infection is very common, identification of patients during acute infection is rare. Consequently, little is known about the immune response during this critical stage of the disease. We analyzed the T lymphocyte response during and after acute resolving HCV infection in three persons, using interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and human histocompatibility leukocyte antigen (HLA) peptide tetramer assays. Acute infection was associated with a broadly directed T helper and cytotoxic T lymphocyte (CTL) response, which persisted after resolution of clinical hepatitis and clearance of viremia. At the earliest time point studied, highly activated CTL populations were observed that temporarily failed to secrete IFN-γ, a “stunned” phenotype, from which they recovered as viremia declined. In long-term HCV-seropositive persons, CTL responses were more common in persons who had cleared viremia compared with those with persistent viremia, although the frequencies of HCV-specific CTLs were lower than those found in persons during and after resolution of acute HCV infection. These studies demonstrate a strong and persistent CTL response in resolving acute HCV infection, and provide rationale to explore immune augmentation as a therapeutic intervention in chronic HCV infection.

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Phenotypic and Functional Changes of Cytotoxic CD56pos Natural T Cells Determine Outcome of Acute Hepatitis C Virus Infection

Journal of Virology ◽

10.1128/jvi.00834-07 ◽

2007 ◽

Vol 81 (17) ◽

pp. 9292-9298 ◽

Cited By ~ 43

Author(s):

Lucy Golden-Mason ◽

Nicole Castelblanco ◽

Cliona O'Farrelly ◽

Hugo R. Rosen

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Spontaneous Recovery ◽

Acute Infection ◽

Hcv Infection ◽

Receptor Expression ◽

Acute Hepatitis C ◽

Functional Changes ◽

Acute Hcv ◽

Acute Hcv Infection

ABSTRACT Innate CD56pos natural killer (NK) and natural T (NT) cells comprise important hepatic antiviral effector lymphocytes whose activity is fine-tuned through surface NK receptors (NKRs). Dysregulation of NKRs in patients with long-standing hepatitis C virus (HCV) infection has been shown, but little is known regarding NKRs in acute infection. Treatment-naïve patients with acute HCV (n = 22), including 10 with spontaneous recovery, were prospectively studied. CD56pos NT levels were reduced early in acute HCV infection and did not fluctuate over time. In resolving HCV infection, NT cells with a more activated phenotype (lower CD158A and higher natural cytotoxicity receptor expression) at baseline predated spontaneous recovery. Moreover, NKG2A expression on CD56+ NT cells correlated directly with circulating HCV RNA levels. Deficient interleukin-13 (IL-13) production by NT cells and reduced IL-2-activated killing (LAK) at baseline were associated with the ultimate development of persistence. These results indicate a previously unappreciated role for NT cells in acute HCV infection and identify a potential target for pharmacologic manipulation.

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PD-1 Expression in Acute Hepatitis C Virus (HCV) Infection Is Associated with HCV-Specific CD8 Exhaustion

Journal of Virology ◽

10.1128/jvi.01177-06 ◽

2006 ◽

Vol 80 (22) ◽

pp. 11398-11403 ◽

Cited By ~ 399

Author(s):

Simona Urbani ◽

Barbara Amadei ◽

Daniela Tola ◽

Marco Massari ◽

Simona Schivazappa ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Cell Function ◽

Hcv Infection ◽

Acute Hepatitis C ◽

Inhibitory Receptor ◽

Cd8 Cells ◽

Acute Hcv ◽

Cd8 Cell ◽

Acute Hcv Infection

ABSTRACT Hepatitis C virus (HCV)-specific CD8 cell exhaustion may represent a mechanism of HCV persistence. The inhibitory receptor PD-1 has been reported to be up-regulated in exhausted CD8 cells. Therefore, we studied PD-1 expression longitudinally during acute HCV infection. Most HCV-specific CD8 cells expressed PD-1 at the time of acute illness, irrespective of the final outcome. PD-1 expression declined with the acquisition of a memory phenotype and recovery of an efficient CD8 cell function in resolving HCV infections, whereas high levels were maintained when HCV persisted and HCV-specific CD8 cells remained dysfunctional. Blocking PD-1/PDL-1 interaction with an anti-PDL-1 antibody improved the capacity of expansion of virus-specific CD8 cells.

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High Level of PD-1 Expression on Hepatitis C Virus (HCV)-Specific CD8+ and CD4+ T Cells during Acute HCV Infection, Irrespective of Clinical Outcome

Journal of Virology ◽

10.1128/jvi.00376-11 ◽

2011 ◽

Vol 85 (9) ◽

pp. 4633-4633

Author(s):

V. Kasprowicz ◽

J. S. zur Wiesch ◽

T. Kuntzen ◽

B. E. Nolan ◽

S. Longworth ◽

...

Keyword(s):

T Cells ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Clinical Outcome ◽

Cd4 T Cells ◽

Hcv Infection ◽

Acute Hcv ◽

High Level ◽

Acute Hcv Infection

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O22.2 Detection of hepatitis c virus (hcv) in semen from hiv-infected men who have sex with men (msm) during acute hcv infection

Sexually Transmitted Infections ◽

10.1136/sextrans-2015-052270.198 ◽

2015 ◽

Vol 91 (Suppl 2) ◽

pp. A74.2-A75

Author(s):

S Turner ◽

M Yip ◽

D Smith ◽

S Weibel ◽

W van Seggelen ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Hcv Infection ◽

Acute Hcv ◽

Sex With Men ◽

Acute Hcv Infection

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Impaired Hepatitis C Virus (HCV)-Specific Effector CD8+ T Cells Undergo Massive Apoptosis in the Peripheral Blood during Acute HCV Infection and in the Liver during the Chronic Phase of Infection

Journal of Virology ◽

10.1128/jvi.01075-08 ◽

2008 ◽

Vol 82 (20) ◽

pp. 9808-9822 ◽

Cited By ~ 69

Author(s):

Henry Radziewicz ◽

Chris C. Ibegbu ◽

Huiming Hon ◽

Melissa K. Osborn ◽

Kamil Obideen ◽

...

Keyword(s):

T Cells ◽

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Chronic Phase ◽

T Cell Response ◽

Hcv Infection ◽

Caspase 9 ◽

Acute Hcv ◽

Acute Hcv Infection

ABSTRACT A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8+ T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8+ T cells during the acute and chronic stages of infection. Although HCV-specific CD8+ T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8+ T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCV-specific CD8+ T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the “death phase” of HCV-specific CD8+ T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections.

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Acute hepatitis C virus infection

Eurosurveillance ◽

10.2807/ese.13.21.18879-en ◽

2008 ◽

Vol 13 (21) ◽

Cited By ~ 14

Author(s):

W L Irving ◽

D Salmon ◽

C Boucher ◽

I M Hoepelman

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Hcv Infection ◽

Acute Hepatitis C ◽

Acute Hcv ◽

Chronic Hcv Infection ◽

Chronic Hcv ◽

The Individual ◽

Acute Hcv Infection ◽

Subsequent Risk

Around 25% of people infected with hepatitis C virus (HCV) are able to clear the infection spontaneously, while the majority become chronically infected, with a subsequent risk for the individual patient of progressive inflammatory liver disease, cirrhosis, hepatocellular carcinoma and liver-related death (Figure 1). Much is known about the epidemiology, pathogenesis, diagnosis and management of chronic HCV infection. In comparison, knowledge about acute HCV infection is patchy. In this article, we will highlight concerns relating to acute HCV infection and suggest that public health bodies responsible for managing the HCV epidemic should redirect at least some of their resources to dealing with these issues.

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Pathogen-Associated Molecular Pattern Recognition of Hepatitis C Virus Transmitted/Founder Variants by RIG-I Is Dependent on U-Core Length

Journal of Virology ◽

10.1128/jvi.01964-15 ◽

2015 ◽

Vol 89 (21) ◽

pp. 11056-11068 ◽

Cited By ~ 19

Author(s):

Alison Kell ◽

Mark Stoddard ◽

Hui Li ◽

Joe Marcotrigiano ◽

George M. Shaw ◽

...

Keyword(s):

Innate Immunity ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Acute Infection ◽

Innate Immune ◽

Hcv Infection ◽

Immune Signaling ◽

Molecular Pattern ◽

Innate Immune Signaling ◽

Acute Hcv

ABSTRACTDespite the introduction of direct-acting antiviral (DAA) drugs against hepatitis C virus (HCV), infection remains a major public health concern because DAA therapeutics do not prevent reinfection and patients can still progress to chronic liver disease. Chronic HCV infection is supported by a variety of viral immune evasion strategies, but, remarkably, 20% to 30% of acute infections spontaneously clear prior to development of adaptive immune responses, thus implicating innate immunity in resolving acute HCV infection. However, the virus-host interactions regulating acute infection are unknown. Transmission of HCV involves one or a few transmitted/founder (T/F) variants. In infected hepatocytes, the retinoic acid-inducible gene I (RIG-I) protein recognizes 5′ triphosphate (5′ppp) of the HCV RNA and a pathogen-associated molecular pattern (PAMP) motif located within the 3′ untranslated region consisting of poly-U/UC. PAMP binding activates RIG-I to induce innate immune signaling and type 1 interferon antiviral defenses. HCV poly-U/UC sequences can differ in length and complexity, suggesting that PAMP diversity in T/F genomes could regulate innate immune control of acute HCV infection. Using 14 unique poly-U/UC sequences from HCV T/F genomes recovered from acute-infection patients, we tested whether RIG-I recognition and innate immune activation correlate with PAMP sequence characteristics. We show that T/F variants are recognized by RIG-I in a manner dependent on length of the U-core motif of the poly-U/UC PAMP and are recognized by RIG-I to induce innate immune responses that restrict acute infection. PAMP recognition of T/F HCV variants by RIG-I may therefore impart innate immune signaling and HCV restriction to impact acute-phase-to-chronic-phase transition.IMPORTANCERecognition of nonself molecular patterns such as those seen with viral nucleic acids is an essential step in triggering the immune response to virus infection. Innate immunity is induced by hepatitis C virus infection through the recognition of viral RNA by the cellular RIG-I protein, where RIG-I recognizes a poly-uridine/cytosine motif in the viral genome. Variation within this motif may provide an immune evasion strategy for transmitted/founder viruses during acute infection. Using 14 unique poly-U/UC sequences from HCV T/F genomes recovered from acutely infected HCV patients, we demonstrate that RIG-I binding and activation of innate immunity depend primarily on the length of the uridine core within this motif. T/F variants found in acute infection contained longer U cores within the motif and could activate RIG-I and induce innate immune signaling sufficient to restrict viral infection. Thus, recognition of T/F variants by RIG-I could significantly impact the transition from acute to chronic infection.

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Initial Presentation of Acute Hepatitis C Virus (HCV) Infection among HIV–Negative and HIV‐Positive Individuals—Experience from 2 Large German Networks on the Study of Acute HCV Infection

Clinical Infectious Diseases ◽

10.1086/600058 ◽

2009 ◽

Vol 49 (2) ◽

pp. 317-319 ◽

Cited By ~ 38

Author(s):

Martin Vogel ◽

Katja Deterding ◽

Johannes Wiegand ◽

Norbert H. Grüner ◽

Axel Baumgarten ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Acute Hepatitis ◽

Hcv Infection ◽

Initial Presentation ◽

Hiv Positive ◽

Acute Hepatitis C ◽

Acute Hcv ◽

Acute Hcv Infection ◽

Hiv Negative

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Detection of host immune responses in acute phase sera of spontaneous resolution versus persistent hepatitis C virus infection

Journal of General Virology ◽

10.1099/vir.0.041277-0 ◽

2012 ◽

Vol 93 (8) ◽

pp. 1673-1679 ◽

Cited By ~ 5

Author(s):

Suganya Selvarajah ◽

Sheila Keating ◽

John Heitman ◽

Kai Lu ◽

Graham Simmons ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Immune Responses ◽

Serum Levels ◽

Hcv Infection ◽

Serum Samples ◽

Necrosis Factor Alpha ◽

Acute Hcv ◽

Chronic Hcv ◽

Acute Hcv Infection

Prior to the identification of hepatitis C virus (HCV), transfusion-transmission was common. Viral transmission in subjects with a known date of infection allows the study of the immune responses to acute HCV infection. We analysed 39 soluble immune factors in serum samples from subjects with transfusion-transmitted HCV. Dynamic expression kinetics of interferon gamma-induced protein 10 (IP-10), tumour necrosis factor-alpha and interleukin (IL)-10 were observed during acute HCV infection. Serum IP-10 was the only analyte that was significantly elevated in HCV resolvers compared with uninfected controls. In individuals who progressed to chronic HCV elevated levels of IP-10 and IL-10 coincided with first significant alanine aminotransferase elevation and remained elevated during the first year of acute HCV infection. In addition to monitoring lack of reduction in viral load, serum levels of IP-10 and IL-10 expression during acute HCV infection may be useful biomarkers to predict the progress to chronic HCV.

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