Circulating Toll‐like receptor (TLR) 2, TLR4, and regulatory T cells in patients with chronic hepatitis C

Wang, Jiuping; Zhang, Ye; Wei, Xin; Li, Jun; Nan, Xue-Ping; Yu, Haitao; Liu, Yu; Wang, Pingzhong; Bai, Xue–Fan

doi:10.1111/j.1600-0463.2010.02586.x

Cited by 44 publications

(44 citation statements)

References 29 publications

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“…NSC 78206 (cluster 3), also known as cyclobenzaprine, is a muscle relaxant used to relieve skeletal muscle spasms in acute musculoskeletal conditions (64). NSC 78206 is a tricyclic analog compound, which may be relevant because tricyclics and their active metabolites have been shown to have various biological functions, such as modulation of TLR4 and TLR2 signaling (36), whose expression and signaling are known to affect HCV (33,50,76) and inhibition of the drug-metabolizing enzyme aldehyde oxidase (55). In this study, we found that NSC 78206 inhibited JFHpp entry ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Also notable is the tricyclic compound NSC 78206 (c3), as tricyclics or their active metabolites are believed to exert their biological actions, in part, via modulation of Toll-like receptor 4 (TLR4) and TLR2 signaling (36). Likewise, HCV infection correlates with TLR expression and signaling (33,50,76). Because this available information collectively highlighted that each of the 18 compounds identified could potentially affect HCV at distinct and multiple steps during infection, we proceeded to determine the steps inhibited by each of the candidate compounds.…”

Section: Screening Of Anti-hcv Compounds Using a Cell-based Hcvcc Infmentioning

confidence: 99%

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Identification of Hepatitis C Virus Inhibitors Targeting Different Aspects of Infection Using a Cell-Based Assay

Sáinz

Petukhov

et al. 2012

Antimicrob Agents Chemother

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With 2 to 3% of the worldwide population chronically infected, hepatitis C virus (HCV) infection continues to be a major health care burden. Unfortunately, current interferon-based treatment options are not effective in all patients and are associated with significant side effects. Consequently, there is an ongoing need to identify and develop new anti-HCV therapies. Toward this goal, we previously developed a cell-based HCV infection assay for antiviral compound screening based on a low-multiplicity-of-infection approach that uniquely allows for the identification of antiviral compounds that target cell culture-derived HCV (HCVcc) at any step of the viral infection cycle. Using this assay, here we report the screening of the NCI Diversity Set II library, containing 1,974 synthesized chemical compounds, and the identification of compounds with specific anti-HCV activity. In combination with toxicity counterscreening, we identified 30 hits from the compound library, 13 of which showed reproducible and dose-dependent inhibition of HCV with mean therapeutic indices (50% cytotoxic concentration [CC 50 ]/50% effective concentration [EC 50 ]) of greater than 6. Using HCV pseudotype and replicon systems of multiple HCV genotypes, as well as infectious HCVcc-based assembly and secretion analysis, we determined that different compounds within this group of candidate inhibitors target different steps of viral infection. The compounds identified not only will serve as biological probes to study and further dissect the biology of viral infection but also should facilitate the development of new anti-HCV therapeutic treatments. Hepatitis C virus (HCV) is a hepatotropic enveloped positivestrand RNA virus (family Flaviviridae) that infects the parenchymal cells of the liver (i.e., hepatocytes) (69, 70). HCV infection begins with interaction of the viral particle with the target cell via a relatively undefined multistep process of binding between the virion and multiple cell surface receptors, which include the cluster of differentiation 81 (CD81) tetraspanin protein (7,34,56,80,84), the scavenger receptor class B member I (SR-BI) (also known as SCARB1) (7,30,38,63,83), and the tight-junction proteins claudin-1 (CLDN1) (20) and occludin (OCLN) (8,47,57). In addition to these four host factors, we more recently showed that the cellular Niemann-Pick C1-like 1 (NPC1L1) cholesterol uptake receptor also functions as an HCV entry factor via a virion particle cholesterol-associated mechanism (60), and Lupberger et al. have recently shown that the host cellular epidermal growth factor receptor (EGFR) and ephrin receptor A2 (EphA2) function as cofactors during viral cell entry (49).Following entry, the viral genome (ϳ9.6 kb) is translated by an internal ribosome entry site (IRES)-dependent process into a single viral polyprotein that is subsequently co-and posttranslationally cleaved into structural (core, E1, E2, and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins by host and viral proteases (29,46). The NS prote...

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Section: Discussionmentioning

confidence: 99%

Section: Screening Of Anti-hcv Compounds Using a Cell-based Hcvcc Infmentioning

confidence: 99%

Identification of Hepatitis C Virus Inhibitors Targeting Different Aspects of Infection Using a Cell-Based Assay

Sáinz

Petukhov

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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“…Using a coculture system, Shankar et al (2010) found that the priming of Tcells by DCs pulsed with HIV caused an upregulation of an array of negative costimulatory molecules on T-cells and increased expression of CTLA-4 and FOXP3 when compared to priming with mockpulsed DCs. Wang et al (2010) studied 31 chronic hepatitis C patients and 20 healthy controls, and found significant correlations between TLR2 and Treg numbers. These data suggested that Nef induced TLR2 up-regulation could mediate Tregs expansion.…”

Section: Discussionmentioning

confidence: 96%

Human immunodeficiency virus type 1 Nef in human monocyte-like cell line THP-1 expands treg cells via toll-like receptor 2

et al. 2011

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CD4(+) CD25(+) regulatory T cells (Tregs) represent a unique T-cell lineage that is endowed with the ability to actively suppress immune responses in order to inhibit pathogenic damage resulting from over activation of the immune system. In human immunodeficiency virus-1 (HIV-1) infection, suppression of the immune response by Tregs appears to play an opposing role that promotes chronic viral infection. Treg expansion is known as a marker of the severity of HIV infection and as a potential prognostic marker of disease progression. HIV-1 Nef is one of the earliest expressed viral regulatory genes whose expression may play an important role in regulating Treg cells. We established a THP-1 cell line stably expressing HIV-1 Nef and showed that Nef protein was a potent factor for increasing Treg numbers in vitro. We further found that TLR2 plays a critical role in the increase in Treg cells induced by Nef using TLR2-specific siRNA. Our results suggest new strategies for therapeutic and preventive interventions of HIV infection.

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“…These Treg were characterized by a fully differentiated and highly activated phenotype, although approximately half of them did not express CD25. Several studies have reported a correlation between viral load and Treg levels during chronic infection, even though this is not always the case [32,[35][36][37].…”

Section: Hcv Infection and Tregmentioning

confidence: 93%

Role of regulatory T-cells during hepatitis C infection: From the acute phase to post-transplantation recurrence

Barjon

Dahlqvist

Calmus

et al. 2015

Digestive and Liver Disease

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Hepatitis C viral infection persists and becomes chronic in a majority of affected individuals. Numerous factors have been described to explain how the virus manages to escape the host immune system. One important escape mechanism is the increase in regulatory T cells induced by the virus. In this review, we will focus on the status of regulatory T cells throughout the natural history of hepatitis C infection and after liver transplantation. The molecular mechanisms involved in increasing the number of regulatory T cells are also discussed, as are data regarding the impact of regulatory T-cells on hepatic fibrosis in the context of hepatitis C viral infection.

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Circulating Toll‐like receptor (TLR) 2, TLR4, and regulatory T cells in patients with chronic hepatitis C

Cited by 44 publications

References 29 publications

Identification of Hepatitis C Virus Inhibitors Targeting Different Aspects of Infection Using a Cell-Based Assay

Identification of Hepatitis C Virus Inhibitors Targeting Different Aspects of Infection Using a Cell-Based Assay

Human immunodeficiency virus type 1 Nef in human monocyte-like cell line THP-1 expands treg cells via toll-like receptor 2

Role of regulatory T-cells during hepatitis C infection: From the acute phase to post-transplantation recurrence

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