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

Kasprowicz, Victoria; Wiesch, Julian Schulze zur; Kuntzen, Thomas; Nolan, Brian E.; Longworth, S; Berical, Andrew; Blum, Jenna; McMahon, Cory; Reyor, Laura L.; Elias, Nahel; Kwok, William W.; McGovern, Barbara; Freeman, Gordon J.; Chung, Raymond T.; Klenerman, Paul; Lewis-Ximenez, Lia Laura; Walker, Bruce D.; Allen, Todd M.; Kim, Arthur Y.; Lauer, Georg M.

doi:10.1128/jvi.02474-07

Cited by 183 publications

(122 citation statements)

References 15 publications

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“…In this study, high PD-1 expression levels on HCV-specific CD8+ T cells were linked with a chronic evolution of infection [51]. These data are in contrast to other studies, however, that demonstrated a high PD-1 expression of HCV-specific CD8+ T cells in acute HCV infection irrespective of infection outcome [46,52]. These findings parallel the earlier observation that HCV-specific CD8+ T cells have little functional capability during early acute infection (previously referred to as ‘stunned’ phenotype), but regain function in individuals that clear infection [15,18,19].…”

Section: Hcv-specific T Cell Responses In Acute Hcv Infection: Mechancontrasting

confidence: 55%

Success and Failure of Virus-Specific T Cell Responses in Hepatitis C Virus Infection

Thimme¹

2011

Dig Dis

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Hepatitis C virus (HCV) infection is only cleared in a minority of infected individuals, the majority of patients develop chronic infection. Chronic HCV infection potentially leads to liver fibrosis, cirrhosis and finally hepatocellular carcinoma. The host immune response is an important determinant in the outcome of HCV infection. Innate as well as adaptive cellular and humoral immune responses mediate important antiviral actions; however, virus-specific T cell responses appear to be most critical. Indeed, strong and multispecific CD4+ as well as CD8+ T cell responses are required for viral clearance. Interestingly, individuals who express certain HLA alleles (which are important for antigen presentation to CD4+ and CD8+ T cells) have a higher chance to clear the virus. The mechanisms of protection by HLA class I alleles such as HLA-B27 have been characterized recently. In most individuals, however, the HCV-specific immune response fails to clear the virus. Several mechanisms underlying this HCV-specific T cell failure have been identified. These include viral factors such as viral escape mutations and immunological factors such as the expression of inhibitory receptors, which lead to CD8+ T cell dysfunction. An in-depth understanding of the determinants of success or failure of the HCV-specific T cell response is critical for the development of prophylactic as well as therapeutic vaccination regimes against HCV. Here, we will discuss the virological and immunological determinants of HCV clearance and persistence.

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Section: Hcv-specific T Cell Responses In Acute Hcv Infection: Mechancontrasting

confidence: 55%

Success and Failure of Virus-Specific T Cell Responses in Hepatitis C Virus Infection

Thimme¹

2011

Dig Dis

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“…Kasprowicz et al showed that PD-1 expression was high in acute infection and most CD4 ϩ T-cells continued to express PD-1 if virus persisted. 27 Elevated PD-1 expression on virusspecific CD4 ϩ T cells was also described during HIV infection. 6 Importantly, PD-1 expression was down-regulated on virusspecific CD4 ϩ T cells of self-limiting influenza and latently persisting EBV infection, which underlines the negative regulatory role of PD-1 during HCV persistence.…”

Section: Discussionmentioning

confidence: 97%

Inhibitory Molecules That Regulate Expansion and Restoration of HCV-Specific CD4+ T Cells in Patients With Chronic Infection

et al. 2011

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“…Hepacivirus infection induces a potent T cell response, and CD4 ϩ T cells upregulate PD-1 acutely after GBV-B infection, which is indicative of activation; a similar PD-1 ϩ T cell activation is observed in early HCV infection (15)(16)(17)(18). Acute GBV-B infection is also characterized by an influx of CD8 T cells into the liver (9), and clearance of GBV-B has previously been associated with strong responses against the NS3 protein (14).…”

mentioning

confidence: 82%

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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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

Cited by 183 publications

References 15 publications

Success and Failure of Virus-Specific T Cell Responses in Hepatitis C Virus Infection

Success and Failure of Virus-Specific T Cell Responses in Hepatitis C Virus Infection

Inhibitory Molecules That Regulate Expansion and Restoration of HCV-Specific CD4+ T Cells in Patients With Chronic Infection

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

Cited by 183 publications

References 15 publications

Success and Failure of Virus-Specific T Cell Responses in Hepatitis C Virus Infection

Success and Failure of Virus-Specific T Cell Responses in Hepatitis C Virus Infection

Inhibitory Molecules That Regulate Expansion and Restoration of HCV-Specific CD4+ T Cells in Patients With Chronic Infection

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

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Product

Resources

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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