N-glycosylation-mutated HCV envelope glycoprotein complex enhances antigen-presenting activity and cellular and neutralizing antibody responses

Ren, Yushan; Min, Yuan-Qin; Liu, Min; Chi, Lianli; Zhao, Ping; Zhang, Xiaolian

doi:10.1016/j.bbagen.2015.08.007

Cited by 19 publications

(13 citation statements)

References 52 publications

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“…To determine the expression levels of inflammation factors ( IFN‐γ , TNF‐α , IL‐17A , IL‐6 , and IL‐1β ), mice sera were collected at different time points from each group and analysed by elisa following methods from previous studies (Ren et al, ; Zhao et al, ). To investigate the levels of proteins in the TLR4‐related signalling pathway, such as TLR4, phospho‐NF‐κB p65 (p‐p65) or nonphospho‐NF‐κB p65 (p65), JNK, p‐JNK, p38, p‐p38, p21, c‐Jun , , and cleaved caspase‐3, kidney‐paraffin blocks and tissues were subjected to immunohistochemistry, immunofluorescence, and immunoblot analysis.…”

Section: Methodsmentioning

confidence: 99%

Loganetin protects against rhabdomyolysis‐induced acute kidney injury by modulating the toll‐like receptor 4 signalling pathway

Tan

Wang

et al. 2019

British J Pharmacology

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Background and Purpose: Acute kidney injury (AKI) is a rapid renal dysfunctional disease, for which no effective drugs or therapies are available to improve prognosis.Loganetin is a natural product with unknown bioactivities. Here, we identified a new protective effect and mechanism of Loganetin in a mouse model of AKI induced by rhabdomyolysis.Experimental Approach: AKI was induced using glycerol by i.m. injection in mice models. Thirty minutes and 24 and 48 hr after injection of glycerol, the mice received 2 and 18 mg·kg −1 of Loganetin i.p. respectively. Then mice blood and kidney were collected for various biochemical and histopathological studies. Mechanistic studies on modulation of AKI by Loganetin were performed using HK-2 cells and Toll-like receptor 4 (TLR4) knockout mice.Key Results: In the Loganetin treated group, kidney damage and mortality rate were declined, and blood urea nitrogen and serum creatinine were much lower. Loganetin prevented damage to the tubular structures induced by glycerol and decreased apoptotic cells at the corticomedullary junction. In HK-2 cells, Loganetin could inhibit NF-κB pathway and pro-apoptotic genes expression. However, TLR4 was silenced by a specific shRNA, and the inhibitory effect of Loganetin in HK-2 cells vanished. Loganetin also down-regulated the expression of inflammation factors by suppressing TLR4 activity.Conclusion and Implications: All the results suggested that TLR4 plays a critical role in AKI development, and Loganetin ameliorates AKI by inhibiting TLR4 activity and blocking the JNK/p38 pathway, which provides a new strategy for AKI treatment.

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Section: Methodsmentioning

confidence: 99%

Loganetin protects against rhabdomyolysis‐induced acute kidney injury by modulating the toll‐like receptor 4 signalling pathway

Tan

Wang

et al. 2019

British J Pharmacology

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“…A more promising approach would be to modify existing vaccine candidates, such as E1/E2 or soluble E2, to increase the exposition of AR3A while potentially decreasing the availability of other epitopes that either are poorly conserved or have low barriers to resistance. Such approaches have already provided some success for HCV (62)(63)(64) and for HIV vaccine candidates (65), but these approaches would benefit greatly from a better understanding of the E1/E2 protein complex.…”

Section: Fig 17mentioning

confidence: 99%

Hepatitis C Virus Escape Studies of Human Antibody AR3A Reveal a High Barrier to Resistance and Novel Insights on Viral Antibody Evasion Mechanisms

Velázquez-Moctezuma

Galli

Law

et al. 2019

J Virol

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Yearly, ϳ2 million people become hepatitis C virus (HCV) infected, resulting in an elevated lifetime risk for severe liver-related chronic illnesses. Characterizing epitopes of broadly neutralizing antibodies (NAbs), such as AR3A, is critical to guide vaccine development. Previously identified alanine substitutions that can reduce AR3A binding to expressed H77 envelope were introduced into chimeric cell culture-infectious HCV recombinants (HCVcc) H77(core-NS2)/JFH1. Substitutions G523A, G530A, and D535A greatly reduced fitness, and S424A, P525A, and N540A, although viable, conferred only low-level AR3A resistance. Using highly NAb-sensitive hypervariable region 1 (HVR1)-deleted HCVcc, H77/JFH1 ΔHVR1 and J6(core-NS2)/JFH1 ΔHVR1 , we previously reported a low barrier to developing AR5A NAb resistance substitutions. Here, we cultured Huh7.5 cells infected with H77/JFH1, H77/JFH1 ΔHVR1 , or J6/ JFH1 ΔHVR1 with AR3A. We identified the resistance envelope substitutions M345T in H77/JFH1, L438S and F442Y in H77/JFH1 ΔHVR1 , and D431G in J6/JFH1 ΔHVR1 . M345T increased infectivity and conferred low-level AR3A resistance to H77/JFH1 but not H77/JFH1 ΔHVR1 . L438S and F442Y conferred high-level AR3A resistance to H77/ JFH1 ΔHVR1 but abrogated the infectivity of H77/JFH1. D431G conferred AR3A resistance to J6/JFH1 ΔHVR1 but not J6/JFH1. This was possibly because D431G conferred broadly increased neutralization sensitivity to J6/JFH1 D431G but not J6/JFH1 ΔHVR1/D431G while decreasing scavenger receptor class B type I coreceptor dependency. Common substitutions at positions 431 and 442 did not confer high-level resistance in other genotype 2a recombinants [JFH1 or T9(core-NS2)/JFH1]. Although the data indicate that AR3A has a high barrier to resistance, our approach permitted identification of low-level resistance substitutions. Also, the HVR1-dependent effects on AR3A resistance substitutions suggest a complex role of HVR1 in virus escape and receptor usage, with important implications for HCV vaccine development. IMPORTANCE Hepatitis C virus (HCV) is a leading cause of liver-related mortality, and limited treatment accessibility makes vaccine development a high priority. The vaccine-relevant cross-genotype-reactive antibody AR3A has shown high potency, but the ability of the virus to rapidly escape by mutating the AR3A epitope (barrier to resistance) remains unexplored. Here, we succeeded in inducing only low-level AR3A resistance, indicating a higher barrier to resistance than what we have previously reported for AR5A. Furthermore, we identify AR3A resistance substitutions that have hypervariable region 1 (HVR1)-dependent effects on HCV viability and on broad neutralization sensitivity. One of these substitutions increased envelope breathing and decreased scavenger receptor class B type I HCV coreceptor dependency, both in an HVR1-dependent fashion. Thus, we identify novel AR3A-specific resistance substitutions and the role of HVR1 in protecting HCV from AR3-targeting antibodies. Citation Velázquez-Moctezuma R, Galli A, La...

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“…Several engineered E1, E2 and E1E2 antigens have been recently described [32,86,87], including structure-based epitope designs [88,89], the majority of which were tested for immunogenicity in mice, though varying conditions (e.g. protein versus DNA, adjuvant, vaccine dosage and schedule) and immunological readouts prevent a direct comparison of results from these designed antigens.…”

Section: Rational Design Of An Hcv Vaccinementioning

confidence: 99%

Viral evasion and challenges of hepatitis C virus vaccine development

Pierce

Keck

Foung

2016

Current Opinion in Virology

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Hepatitis C virus (HCV) is a major global disease burden, often leading to chronic liver diseases, cirrhosis, cancer, and death in those infected. Despite the recent approval of antiviral therapeutics, a preventative vaccine is recognized as the most effective means to control HCV globally, particularly in at-risk and developing country populations. Here we describe the efforts and challenges related to the development of an HCV vaccine, which after decades of research have not been successful. Viral sequence variability poses a major challenge, yet recent research has provided unprecedented views of the atomic structure of HCV epitopes and immune recognition by antibodies and T cell receptors. This, coupled with insights from deep sequencing, robust neutralization assays, and other technological advances, is spurring research toward rationally HCV designed vaccines that preferentially elicit responses toward conserved epitopes of interest that are associated with viral neutralization and clearance.

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N-glycosylation-mutated HCV envelope glycoprotein complex enhances antigen-presenting activity and cellular and neutralizing antibody responses

Cited by 19 publications

References 52 publications

Loganetin protects against rhabdomyolysis‐induced acute kidney injury by modulating the toll‐like receptor 4 signalling pathway

Loganetin protects against rhabdomyolysis‐induced acute kidney injury by modulating the toll‐like receptor 4 signalling pathway

Hepatitis C Virus Escape Studies of Human Antibody AR3A Reveal a High Barrier to Resistance and Novel Insights on Viral Antibody Evasion Mechanisms

Viral evasion and challenges of hepatitis C virus vaccine development

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