<scp>HBV</scp> coinfection with <scp>HCV</scp> alters circulating Tfh cell distribution and impairs <scp>HCV</scp> neutralizing antibody responses

Wen, Bo; Zhang, Jian; Liu, Wenpei; Tang, Ping; Xie, Ting; Huang, Liyan; Hu, Yabin; Jin, Kui; Zhang, Ping; Liu, Ziyan; Niu, Ling; Qu, Xiaowang

doi:10.1111/jvh.13106

Cited by 5 publications

(7 citation statements)

References 47 publications

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“…Collectively, despite the bias of using phenotypically altered in vitro -expanded cells, we could confirm our ex vivo results on HCV-specific CD4 T cells that showed an overlapping Tfh/Th1 phenotype and gene expression profile ( 26 ) and we were able to demonstrate superior Tfh functionality of these cell population on the antigen-specific level. Our results strongly support previous findings that the B cell or the neutralizing antibody response to HCV infection are positively correlated to the Tfh1 rather than Tfh response ( 16 – 18 , 24 ).…”

Section: Discussionsupporting

confidence: 92%

“…One of the most prominent subsets of cTfh cells are those with overlapping Th1 characteristics, often referred to as cTfh1 cells. They have been shown to correlate with antibody responses during infections with HCV and HIV (14)(15)(16)(17)(18)24) and after vaccination (20)(21)(22)(23) and are the dominant subset within circulating HCV-specific CD4 T cells after DAA therapy (26). However, studies of their actual B cell helper capacity were hampered by the scarcity of this cell population and consequently limited to the bulk level.…”

Section: Discussionmentioning

confidence: 99%

“…Human Tfh cells that express the surface receptors CXCR5 and PD-1 but lack the expression of CXCR3 are known as circulating counterparts of germinal center Tfh cells (cTfh), are able to provide help to memory B cells in vitro and are associated with neutralizing HIV antibody responses (12), whereas CXCR3+ Th1biased cTfh (cTfh1) cells may either fail to support memory B cells in vitro (12,13) but have also shown to correlate with antibody responses to HIV (14,15), HCV (16)(17)(18), other viral infections (19) and after vaccination (20)(21)(22)(23) in humans and animal models. Most recently, the early activation of CXCR3+ but not CXCR3-Tfh cells has been associated with more effective antibody responses and resolution of HCV infection (24).…”

Section: Introduction Cd4mentioning

confidence: 99%

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Th1-Biased Hepatitis C Virus-Specific Follicular T Helper-Like Cells Effectively Support B Cells After Antiviral Therapy

et al. 2021

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Circulating Th1-biased follicular T helper (cTfh1) cells have been associated with antibody responses to viral infection and after vaccination but their B cell helper functionality is less understood. After viral elimination, Tfh1 cells are the dominant subset within circulating Hepatitis C Virus (HCV)-specific CD4 T cells, but their functional capacity is currently unknown. To address this important point, we established a clone-based system to evaluate CD4 T cell functionality in vitro to overcome experimental limitations associated with their low frequencies. Specifically, we analyzed the transcription factor expression, cytokine secretion and B cell help in co-culture assays of HCV- (n = 18) and influenza-specific CD4 T cell clones (n = 5) in comparison to Tfh (n = 26) and Th1 clones (n = 15) with unknown antigen-specificity derived from healthy donors (n = 4) or direct-acting antiviral (DAA)-treated patients (n = 5). The transcription factor expression and cytokine secretion patterns of HCV-specific CD4 T cell clones indicated a Tfh1 phenotype, with expression of T-bet and Bcl6 and production of IFN-γ and IL-21. Their B helper capacity was superior compared to influenza-specific or Tfh and Th1 clones. Moreover, since Tfh cells are enriched in the IFN-rich milieu of the HCV-infected liver, we investigated the impact of IFN exposure on Tfh phenotype and function. Type I IFN exposure was able to introduce similar phenotypic and functional characteristics in the Tfh cell population within PBMCs or Tfh clones in vitro in line with our finding that Tfh cells are elevated in HCV-infected patients shortly after initiation of IFN-α therapy. Collectively, we were able to functionally characterize HCV-specific CD4 T cells in vitro and not only confirmed a Tfh1 phenotype but observed superior Tfh functionality despite their Th1 bias. Furthermore, our results suggest that chronic type I IFN exposure supports the enrichment of highly functional HCV-specific Tfh-like cells during HCV infection. Thus, HCV-specific Tfh-like cells after DAA therapy may be a promising target for future vaccination design aiming to introduce a neutralizing antibody response.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introduction Cd4mentioning

confidence: 99%

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Th1-Biased Hepatitis C Virus-Specific Follicular T Helper-Like Cells Effectively Support B Cells After Antiviral Therapy

et al. 2021

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“…A recent study has investigated the impact of co-existing HBV on circulating T follicular helper cell (Tfh) distribution and the HCV neutralizing antibody response [47]. Patients with HCV mono-infection (n = 83) and HBV/HCV co-infection (n = 78) were both enrolled.…”

Section: Viral Interactions: With Emphasis On Mechanisms Of Hbv Reactmentioning

confidence: 99%

Hepatitis C Virus and Hepatitis B Virus Co-Infection

Shih¹,

Liu

2020

Viruses

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Hepatitis C virus (HCV) and hepatitis B virus (HBV) co-infection can be encountered in either virus endemic countries. Co-infection can also be found in populations at risk of parenteral transmission. Previous studies demonstrated a high risk of liver disease progression in patients with HCV/HBV co-infection; thus, they should be treated aggressively. Previous evidence recommended therapy combining peginterferon (pegIFN) alfa and ribavirin for co-infected patients with positive HCV RNA. Recent trials further advise using direct-acting antivirals (DAAs) for the clearance of HCV in the co-infected patients. Reactivation of HBV has been observed in patients post-intervention, with higher risks and earlier onset in those having had HCV cured by DAA- versus pegIFN-based therapy. The mechanism of HBV reactivation is an interesting but unsolved puzzle. Our recent study revealed that in vitro HBV replication was suppressed by HCV co-infection; HBV suppression was attenuated when interferon signaling was blocked. In vivo, the HBV viremia, initially suppressed by the presence of HCV super-infection, rebounded following HCV clearance by DAA treatment and was accompanied by a reduced hepatic interferon response. In summary, major achievements in the treatment of HCV/HBV co-infection have been accomplished over the past 20 years. Future clinical trials should address measures to reduce or prevent HBV reactivation post HCV cure.

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“…The results of Spaan et al (14) showed that the expression of ICOS + Tfh cells and cytokine IL-21 increased significantly in the course of acute HCV infection, suggesting that cTfh cells play a key role in the regulation of immune response to acute HCV infection. Alternatively, IL-21 receptors are widely distributed in B cells and cTfh cells, which can positively promote the expression of CXCR5 in patients with acute hepatitis C through autocrine signaling (9,15,16).…”

Section: Cd4+cxcr5+ctfh Ratio and Hcv Rna Content In Infected Groupmentioning

confidence: 99%

Changes in circulating follicular helper T cells in peripheral blood of patients with acute hepatitis C virus infection

et al. 2020

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Background: To investigate the changes in circulating follicular helper T cells (cTfh) in peripheral blood of patients with acute hepatitis C virus (HCV) infection and its correlation with symptom severity of the disease.Methods: A total of 105 subjects were enrolled in this study, including 35 healthy people, 35 patients with acute HCV infection and 35 acute HCV patients with antiviral therapy. Flow cytometry was used to detect the expression of molecular markers related to the surface of cTfh cells, such as CD69, HLA-DR and CD57, and ELISA was used to detect the secretion of cytokines (IL-21, IL-4) in each group. The relationship between these markers and disease was analyzed statistically.Results: Flow cytometry analysis demonstrated that the percentage of CD69 in peripheral blood of patients with acute hepatitis C infection was (18.90%±9.29%) significantly higher than that of normal control group (5.10%±4.21%) and antiviral treatment group (11.50%±5.38%). The difference was statistically significant (P<0.05). The results of HLA-DR and CD57 were consistent with CD69. The serum levels of IL-4 and IL-21 in the acute HCV infection group were significantly higher than those in the treatment and the control groups. After antiviral treatment, IL-4 and IL-21 levels significantly decreased but remained higher than those in the control group. This showed that antiviral treatment was effective, and the difference was statistically significant (P<0.05). The ratio of cTfh in infected group was negatively correlated with HCV RNA content (r=−0.6858, P=0.0028).Conclusions: Antiviral immune response in patients with acute hepatitis C infection may be related to the proportion of T helper cells in peripheral blood circulation follicles. Dynamic detection of the number of T helper cells in clinical practice is conducive to identifying more effective methods to treat acute hepatitis C infection, which has important theoretical and clinical significance.

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HBV coinfection with HCV alters circulating Tfh cell distribution and impairs HCV neutralizing antibody responses

Cited by 5 publications

References 47 publications

Th1-Biased Hepatitis C Virus-Specific Follicular T Helper-Like Cells Effectively Support B Cells After Antiviral Therapy

Th1-Biased Hepatitis C Virus-Specific Follicular T Helper-Like Cells Effectively Support B Cells After Antiviral Therapy

Hepatitis C Virus and Hepatitis B Virus Co-Infection

Changes in circulating follicular helper T cells in peripheral blood of patients with acute hepatitis C virus infection

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