High-Programmed Death-1 Levels on Hepatitis C Virus-Specific T Cells during Acute Infection Are Associated with Viral Persistence and Require Preservation of Cognate Antigen during Chronic Infection

Rutebemberwa, Alleluiah; Ray, Stuart C.; Astemborski, Jacqueline; Levine, Jordana; Liu, Lin; Dowd, Kimberly A.; Clute, Shalyn Catherine; Wang, Changyu; Korman, Alan J.; Sette, Alessandro; Sidney, John; Pardoll, Drew M.; Cox, Andrea L.

doi:10.4049/jimmunol.181.12.8215

Cited by 113 publications

(91 citation statements)

References 40 publications

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“…HIV-specific T-cell receptormediated stimulation, general immune activation, and direct functional effects of viral particles/proteins could be among the mechanisms that lead to this pervasive expression pattern. 4,[36][37][38] Treatment with ART reduced inhibitory receptor expression, in some cases even to the levels observed on CD8 ϩ T cells from HIV Ϫ persons; this is consistent with previously observed effects of ART on CD8 ϩ T-cell functionality. 39 It is notable that CD160 expression was significantly higher on naive CD8 ϩ T cells from HIV ϩ persons compared with the corresponding cells from HIV Ϫ persons and that this was reversed by ART.…”

Section: Determinants Of Hiv-specific Cd8 ϩ T-cell Exhaustion 4811supporting

confidence: 78%

Surface expression patterns of negative regulatory molecules identify determinants of virus-specific CD8+ T-cell exhaustion in HIV infection

Yamamoto¹,

Price

Casazza³

et al. 2011

Blood

171

224

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A highly complex network of coinhibitory and costimulatory receptors regulates the outcome of virus-specific CD8+ T-cell responses. Here, we report on the expression patterns of multiple inhibitory receptors on HIV-specific, cytomegalovirus-specific, and bulk CD8+ T-cell memory populations. In contrast to cytomegalovirus-specific CD8+ T cells, the majority of HIV-specific CD8+ T cells exhibited an immature phenotype and expressed Programmed Death-1, CD160 and 2B4 but not lymphocyte activation gene-3. Notably, before antiretroviral therapy, simultaneous expression of these negative regulators correlated strongly with both HIV load and impaired cytokine production. Suppression of HIV replication by antiretroviral therapy was associated with reduced surface expression of inhibitory molecules on HIV-specific CD8+ T cells. Furthermore, in vitro manipulation of Programmed Death-1 and 2B4 inhibitory pathways increased the proliferative capacity of HIV-specific CD8+ T cells. Thus, multiple coinhibitory receptors can affect the development of HIV-specific CD8+ T-cell responses and, by extension, represent potential targets for new immune-based interventions in HIV-infected persons.

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Section: Determinants Of Hiv-specific Cd8 ϩ T-cell Exhaustion 4811supporting

confidence: 78%

Surface expression patterns of negative regulatory molecules identify determinants of virus-specific CD8+ T-cell exhaustion in HIV infection

Yamamoto¹,

Price

Casazza³

et al. 2011

Blood

171

224

View full text Add to dashboard Cite

show abstract

“…In this regard, the inhibitory receptor programmed death 1 (PD-1), a CD28 family costimulatory/coinhibitory molecule, is highly expressed on virus-specific exhausted CTLs cells in comparison to functional memory CD8 + T cells and regulates CTL dysfunction (13). The recent observation that PD-1 expression is decreased on HCV-specific CTLs that recognize mutated versus intact viral epitopes (14) underscores a plausible link between the mechanisms of mutational escape and immune exhaustion.…”

Section: Introductionmentioning

confidence: 99%

Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity

McMahan

Golden-Mason²,

Nishimura³

et al. 2010

J. Clin. Invest.

274

248

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Having successfully developed mechanisms to evade immune clearance, hepatitis C virus (HCV) establishes persistent infection in approximately 75%-80% of patients. In these individuals, the function of HCV-specific CD8 + T cells is impaired by ligation of inhibitory receptors, the repertoire of which has expanded considerably in the past few years. We hypothesized that the coexpression of the negative regulatory receptors T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) and programmed death 1 (PD-1) in HCV infection would identify patients at risk of developing viral persistence during and after acute HCV infection. The frequency of PD-1 -Tim-3 -HCV-specific CTLs greatly outnumbered PD-1 + Tim-3 + CTLs in patients with acute resolving infection. Moreover, the population of PD-1 + Tim-3 + T cells was enriched for within the central memory T cell subset and within the liver. Blockade of either PD-1 or Tim-3 enhanced in vitro proliferation of HCV-specific CTLs to a similar extent, whereas cytotoxicity against a hepatocyte cell line that expressed cognate HCV epitopes was increased exclusively by Tim-3 blockade. These results indicate that the coexpression of these inhibitory molecules tracks with defective T cell responses and that anatomical differences might account for lack of immune control of persistent pathogens, which suggests their manipulation may represent a rational target for novel immunotherapeutic approaches.

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“…HCV core has been implicated in this process via binding to the receptor for the globular head domains of complement component C1q (gC1qR) and inhibition of Lck/Akt activation and T cell function (86). Dysfunctional HCV-specific T cells express the inhibitory receptor PD-1 (87,88), which is a direct result of chronic antigenic stimulation and decreases when HCV mutates in T cell epitopes (89). Interaction of PD-1 on T cells with its ligand, PD-L1 (expressed on sinusoidal endothelial cells, Kupffer cells, stellate cells, and type I IFN-exposed hepatocytes in the liver), inhibits effector functions and induces T cell apoptosis (90).…”

Section: Chronic Hcv Infection: Exhaustion Of Hcv-specific T Cellsmentioning

confidence: 99%

Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence

2009

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Historical perspectiveHCV was identified by Choo et al. in 1989 using the then-novel approach of molecular cloning instead of classic virus purification (1). Assays to detect HCV antibodies were introduced less than 3 years later - a significant advance that virtually stopped the transmission of HCV via blood transfusions in the US and reduced the incidence of new cases to less than 40,000 per year, most resulting from injection drug use. Less frequent modes of infection include perinatal transmission (estimated to occur in 2%-8% of babies born to HCV-infected mothers) and sexual transmission, which is much less effective for HCV than for other viruses, such as HIV and HBV, and is rare among people in longterm monogamous relationships (2).Despite advances in the prevention of new HCV infection, more than 4 million individuals infected in the US and more than 120 million worldwide are currently chronically infected. About half do not mount a sustained response to the currently available therapy, a combination of pegylated IFN and ribavirin. The incidence of complications from chronic HCV infection, such as cirrhosis and hepatocellular carcinoma, is therefore predicted to increase (3), possibly reaching the same incidence as in Japan, where widespread distribution of HCV occurred decades earlier than in Western countries (4).From the beginning, HCV research has proven challenging. In the absence of tissue culture and small animal models of infection, the first functional HCV cDNA clones had to be tested in chimpanzees (5). Since then, several models have been developed to study the viral life cycle. The first milestone was the generation of selectable subgenomic HCV replicons that self amplified in transfected hepatoma cells (6). Long-term propagation of replicon-harboring cells resulted in selection for HCV adaptive mutations and increased replication efficiency. However, HCV sequences with in vitro selected, adaptive mutations were not infectious. This was overcome by the isolation of the HCV JFH1 strain from a patient with fulminant hepatitis (7). This strain does not require adaptive mutations to replicate efficiently in hepatoma cell lines with defective IFN responses and maintains its in vivo infectivity (8-10). Several models to study HCV binding and entry were developed in parallel. Virus-like particles produced in the baculovirus system (11) and retroviral pseudoparticles with HCV envelope glycoproteins (12, 13) were used as in vitro models, and immunodeficient mice transplanted with human hepatocytes (14) are now available to screen antibodies and antiviral agents in vivo. The virus and its life cycleHCV is an enveloped, positive-stranded RNA virus and represents the Hepacivirus genus in the Flaviviridae family (15). Six major HCV genotypes and more than 100 subtypes have been identified. In the blood of infected patients, HCV is physically associated with VLDL, LDL, and HDL. Entry into hepatocytes requires the tetraspanin CD81 (16), the scavenger receptor class B type I (17), and the tight junction prot...

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High-Programmed Death-1 Levels on Hepatitis C Virus-Specific T Cells during Acute Infection Are Associated with Viral Persistence and Require Preservation of Cognate Antigen during Chronic Infection

Cited by 113 publications

References 40 publications

Surface expression patterns of negative regulatory molecules identify determinants of virus-specific CD8+ T-cell exhaustion in HIV infection

Surface expression patterns of negative regulatory molecules identify determinants of virus-specific CD8+ T-cell exhaustion in HIV infection

Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity

Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence

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