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

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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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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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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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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Early Interferon Therapy for Hepatitis C Virus Infection Rescues Polyfunctional, Long-Lived CD8+ Memory T Cells

Journal of Virology ◽

10.1128/jvi.01083-08 ◽

2008 ◽

Vol 82 (20) ◽

pp. 10017-10031 ◽

Cited By ~ 105

Author(s):

Gamal Badr ◽

Nathalie Bédard ◽

Mohamed S. Abdel-Hakeem ◽

Lydie Trautmann ◽

Bernard Willems ◽

...

Keyword(s):

T Cells ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Therapeutic Intervention ◽

Memory T Cells ◽

Hcv Infection ◽

Effector Memory ◽

Acute Hepatitis C ◽

Acute Hcv ◽

Acute Hcv Infection

ABSTRACT The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage. Alpha interferon (IFN-α) antiviral therapy achieves the highest rate of success when IFN-α is administered early during the acute phase, but the underlying mechanisms are unknown. We used a panel of major histocompatibility complex class I tetramers to monitor the phenotypic and functional signatures of HCV-specific T cells during acute HCV infection with different infection outcomes and during early IFN therapy. We demonstrate that spontaneous resolution correlates with the early development of polyfunctional (IFN-γ- and IL-2-producing and CD107a+) virus-specific CD8+ T cells. These polyfunctional T cells are distinguished by the expression of CD127 and Bcl-2 and represent a transitional memory T-cell subset that exhibits the phenotypic and functional signatures of both central and effector memory T cells. In contrast, HCV-specific CD8+ T cells in acute infections evolving to chronicity expressed low levels of CD127 and Bcl-2, exhibited diminished proliferation and cytokine production, and eventually disappeared from the periphery. Early therapeutic intervention with pegylated IFN-α rescued polyfunctional memory T cells expressing high levels of CD127 and Bcl-2. These cells were detectable for up to 1 year following discontinuation of therapy. Our results suggest that the polyfunctionality of HCV-specific T cells can be predictive of the outcome of acute HCV infection and that early therapeutic intervention can reconstitute the pool of long-lived polyfunctional memory T cells.

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

Journal of Experimental Medicine ◽

10.1084/jem.191.9.1499 ◽

2000 ◽

Vol 191 (9) ◽

pp. 1499-1512 ◽

Cited By ~ 937

Author(s):

Franziska Lechner ◽

David K.H. Wong ◽

P. Rod Dunbar ◽

Roger Chapman ◽

Raymond T. Chung ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Acute Infection ◽

Hcv Infection ◽

Ctl Response ◽

Acute Hcv ◽

Ifn Γ ◽

Acute Hcv Infection

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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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 infection among adults with HIV in the Netherlands between 2003 and 2016: a capture–recapture analysis for the 2013 to 2016 period

Eurosurveillance ◽

10.2807/1560-7917.es.2020.25.7.1900450 ◽

2020 ◽

Vol 25 (7) ◽

Cited By ~ 1

Author(s):

T. Sonia Boender ◽

Eline Op de Coul ◽

Joop Arends ◽

Maria Prins ◽

Marc van der Valk ◽

...

Keyword(s):

Hepatitis C ◽

The Netherlands ◽

Global Strategy ◽

Hcv Infection ◽

Acute Hepatitis C ◽

Hepatitis C Infection ◽

Acute Hcv ◽

Hiv Serostatus ◽

Capture Recapture ◽

Acute Hcv Infection

Background With regards to the global strategy towards eliminating viral hepatitis, reliable surveillance systems are essential to assess the national response for eliminating hepatitis C virus (HCV). Aim We aimed to assess the completeness of the two national registries with data on acute HCV infection in people with HIV, and estimated the number of acute HCV infections among adults (aged ≥ 18 years) with HIV in the Netherlands. Methods In this observational study, cases of HCV infection and reinfection among adults with a positive or unknown HIV-serostatus were identified from 2003 to 2016 in two national registries: the ATHENA cohort and the National Registry for Notifiable Diseases. For 2013–2016, cases were linked, and two-way capture–recapture analysis was carried out. Results During 2013–2016, there were an estimated 282 (95% confidence interval (CI): 264–301) acute HCV infections among adults with HIV. The addition of cases with an unknown HIV-serostatus increased the matches (from n = 107 to n = 129), and subsequently increased the estimated total: 330 (95%CI: 309–351). Under-reporting was estimated at 14–20%. Conclusion Under-reporting of acute HCV infection among people with HIV could partially be explained by an unknown HIV-serostatus, or by differences in HCV stage (acute or chronic) at first diagnosis. Surveillance data should ideally include both acute and chronic HCV infections, and enable to distinguish these as well as initial- and re-infections. National surveillance of acute HCV can be improved by increased notification of infections.

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