Vaccine-induced early control of hepatitis C virus infection in chimpanzees fails to impact on hepatic PD-1 and chronicity

Rollier, Christine S.; Paranhos-Baccalà, Gláucia; Verschoor, Ernst J.; Verstrepen, Babs E.; Drexhage, Joost; Fagrouch, Zallra; Berland, Jean-Luc; Komurian-Pradel, Florence; Duverger, Blandine; Himoudi, Nourredine; Staib, Caroline; Meyr, Marcus; Whelan, Mike; Whelan, Joseph A.; Adams, Victoria A.; Larrea, Esther; Riezu, J.I.; Lasarte, Juan José; Bartosch, Birke; Cosset, François‐Loïc; Spaan, Willy J. M.; Diepolder, Helmut M.; Pape, Gerd R.; Sutter, Gerd; Inchauspé, Geneviève; Heeney, Jonathan L.

doi:10.1002/hep.21573

Cited by 84 publications

(84 citation statements)

References 56 publications

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“…CD8+ T cells from chimpanzees with persistent HCV infection are also exhausted and express high levels of PD-1 (15,16). Here we report that serial dosing with anti-PD-1 antibodies for several weeks resulted in a significant drop in viremia in one of three treated animals.…”

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confidence: 70%

Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1)

Fuller

Callendret

Zhu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

155

133

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Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti-PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three treated animals without apparent hepatocellular injury. Viremia rebounded in the responder animal when antibody treatment was discontinued. Control of HCV replication was associated with restoration of intrahepatic CD4+ and CD8+ T-cell immunity against multiple HCV proteins. The responder animal had a history of broader T-cell immunity to multiple HCV proteins than the two chimpanzees that did not respond to PD-1 therapy. The results suggest that successful PD-1 blockade likely requires a critical threshold of preexisting virus-specific T cells in liver and warrants consideration of therapeutic vaccination strategies in combination with PD-1 blockade to broaden narrow responses. Anti-PD-1 immunotherapy may also facilitate control of other persistent viruses, notably the hepatitis B virus where options for long-term control of virus replication are limited.

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mentioning

confidence: 70%

Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1)

Fuller

Callendret

Zhu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

155

133

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“…118 Supporting data for the role of PD-1 expression in chronic HCV infection has been recently published with chimpanzees models. 119 However, there are also data suggesting that most intrahepatic CD8 ϩ T cells are toleragenic and express PD-1. 120 One of the evasion mechanisms used by HCV to escape immune responses, especially CD8 responses, is the development of viral escape mutants.…”

Section: Role Of Cd8 T Cellsmentioning

confidence: 99%

Acute hepatitis C virus infection: A chronic problem

et al. 2007

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S ince the discovery of the hepatitis C virus (HCV) in the late 1980s, there has been an explosion of information regarding its natural history, treatment, and replication cycle. Nonetheless, there are still relatively few data regarding acute HCV infection. By convention, the term acute hepatitis refers to the presence of clinical signs or symptoms of hepatitis for a period of 6 months or fewer after the presumed time of HCV exposure. Early studies of posttransfusion patients who developed non-A, non-B hepatitis provide a clinical picture of early infection. 1 Following the availability of specific serologic and virologic tests, most such patients were shown to have acute HCV infection. After acute infection, HCV RNA may become detectable in the serum/plasma in as little as 2 weeks ( Fig. 1). Several weeks later, a high percentage of patients experience an increase in serum aminotransferase levels consistent with the development of acute hepatocellular injury. In the majority of cases, patients develop mild constitutional symptoms, including abdominal pain, nausea, vomiting, anorexia, and fatigue. During this acute infection, serum aminotransferases often peak below 1000 IU/mL and may return to normal levels. A minority develops sufficient elevations in bilirubin to lead to overt jaundice or the development of dark urine. Unless the clinical suspicion is high, few patients will be tested for HCV RNA or HCV antibody seroconversion. However, in the majority-but not all-of infected patients, HCV RNA persists, and a chronic disease state develops.The reasons for the general lack of data regarding acute HCV infection are multifactorial and include (1) the relatively high percentage of asymptomatic or unrecognized early infections, (2) the lack of large-scale identification of chronic carriers in the general population who serve as a reservoir for infection, and (3) the decreased number of acute infections that occur in controlled clinical settings such as that of blood transfusions. These factors and the lack of nonprimate animal models necessitate reliance on retrospective studies in chronic carriers, the use of limited historical collections of banked sera, and the extrapolation of outcomes based on small disease outbreaks in unique settings (for example, transmission from a physician to a patient in the operating room setting or following parenteral exposure in healthcare workers). Moreover, there exist only a limited number of population cohorts that continue to experience high rates of HCV transmission (for example, Egypt); nonetheless, there is a growing body of information regarding the clinical presentation, natural history, and treatment outcomes of acute HCV infection.In this article, we review the current information regarding our understanding of the epidemiology, virology, and immunology of HCV with a particular emphasis on acute HCV infection. In addition, we review recent data related to interferon-based treatment intervention and propose an algorithm for the diagnosis and management of acute HCV inf...

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“…Importantly, the dysfunctionality is clearly reversible in that the depletion of CD25 + regulatory T cells (Tregs) or programmed cell death ligand 1 (PD-L1) ligand-expressing cells restores T cell function in vitro (13,14). This may even have a place in human therapy since PD-L1 + T cells may be increased in vivo during infection (15,16). Overall, this shows that the T cell dysfunction in chronic HCV infection is actively maintained.…”

mentioning

confidence: 99%

Heterologous T Cells Can Help Restore Function in Dysfunctional Hepatitis C Virus Nonstructural 3/4A-Specific T Cells during Therapeutic Vaccination

Chen

Ahlén

Brenndörfer

et al. 2011

The Journal of Immunology

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The hepatitis C virus (HCV)-specific T cell response in patients with chronic HCV is dysfunctional. In this study, we aimed at restoring immunological function through therapeutic vaccination in a transgenic mouse model with impaired HCV-specific T cell responses due to a persistent presence of hepatic HCV nonstructural (NS)3/4A Ags. The HCV-specific T cells have an actively maintained dysfunction reflected in reduced frequency, impaired cytokine production, and impaired effector function in vivo, which can be partially restored by blocking regulatory T cells or programmed cell death ligand 1. We hypothesized that the impairment could be corrected by including sequences that created a normal priming environment by recruiting “healthy” heterologous T cells and by activating innate signaling. Endogenously expressed hepatitis B core Ag (HBcAg) can recruit heterologous T cells and activate TLR (TLR7) signaling. Hence, by combining HCV NS3/4A with different forms of HBcAg we found that heterologous sequences somewhat improved activation and expansion of NS3/4A-specific T cells in a wild-type host. Importantly, the signals provided by HBcAg effectively restored the activation of HCV-specific T cells in a tolerant NS3/4A-transgenic mouse model. The adjuvant effect could also be transferred to the priming of dysfunctional HLA-A2–restricted NS3-specific T cells in vivo. Thus, recruiting healthy heterologous T cells to the site of priming may also help restore HCV-specific responses present in a chronically infected host.

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Vaccine-induced early control of hepatitis C virus infection in chimpanzees fails to impact on hepatic PD-1 and chronicity

Cited by 84 publications

References 56 publications

Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1)

Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1)

Acute hepatitis C virus infection: A chronic problem

Heterologous T Cells Can Help Restore Function in Dysfunctional Hepatitis C Virus Nonstructural 3/4A-Specific T Cells during Therapeutic Vaccination

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