Immunological Dynamics Associated with Direct-Acting Antiviral Therapies in Naive and Experimented HCV Chronic-Infected Patients

Pereira, Grenda Leite; Tarragô, Andréa Monteiro; Neves, Walter Luiz Lima; Souza, Priscila Sarmento de; Affonso, Juliana dos Santos; Sousa, Keyla Santos; Silva, Jéssica Albuquerque da; Costa, Allyson Guimarães; Victoria, Flamir da Silva; Victoria, Marilu Barbieri; Malheiro, Adriana

doi:10.1155/2019/4738237

Cited by 11 publications

(11 citation statements)

References 36 publications

(43 reference statements)

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“…Here, we have measured IFN-Ɣ and IL-2 production of lymphocytes stimulated in vitro, comparing the baseline and FUW12 samples of each patient and found that HCV clearance per se is not sufficient to reverse the decreased production of IFN-Ɣ and IL-2 by HCV-specific T cells, suggesting that prolonged exposure to HCV antigens leads to long-lasting HCV-specific T cells that lack effector functions. Thus, we could show that impaired HCV-specific CD4+ and CD8+ T cells responses during chronic HCV infection are not restored following successful HCV clearance, at least in the short-time after HCV elimination, which is in line with recent published studies [ 25 , 39 , 41 – 43 ].…”

Section: Discussionsupporting

confidence: 91%

“…Regarding the pro-inflammatory cytokines, it has been reported that NK and T cells produce high quantities of IFN-Ɣ and other pro-inflammatory cytokines during acute infections, while production is decreased during chronic infections [ 24 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…Regarding the pro-inflammatory cytokines, it has been reported that NK and T cells produce high quantities of IFN-γ and other pro-inflammatory cytokines during acute infections, while production is decreased during chronic infections [24,40,41]. Interestingly, Sasaki et al reported higher levels of pro-inflammatory cytokines, including IFNγ and IL-2, in serum of rapid virological responders as compared with end of treatment responders, suggesting that enhanced host immune status may contribute in HCV clearance [35].…”

Section: Plos Onementioning

confidence: 99%

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Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy

et al. 2021

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Background & aims HCV CD4+ and CD8+ specific T cells responses are functionally impaired during chronic hepatitis C infection. DAAs therapies eradicate HCV infection in more than 95% of treated patients. However, the impact of HCV elimination on immune responses remain controversial. Here, we aimed to investigate whether HCV cure by DAAs could reverse the impaired immune response to HCV. Methods We analyzed 27 chronic HCV infected patients undergoing DAA treatment in tertiary care hospital, and we determined the phenotypical and functional changes in both HCV CD8+ and CD4+ specific T-cells before and after viral clearance. PD-1, TIM-3 and LAG-3 cell-surface expression was assessed by flow cytometry to determine CD4+ T cell exhaustion. Functional responses to HCV were analyzed by IFN-Ɣ ELISPOT, intracellular cytokine staining (IL-2 and IFN-Ɣ) and CFSE-based proliferation assays. Results We observed a significant decrease in the expression of PD-1 in CD4+ T-cells after 12 weeks of viral clearance in non-cirrhotic patients (p = 0.033) and in treatment-naive patients (p = 0.010), indicating a partial CD4 phenotype restoration. IFN-Ɣ and IL-2 cytokines production by HCV-specific CD4+ and CD8+ T cells remained impaired upon HCV eradication. Finally, a significant increase of the proliferation capacity of both HCV CD4+ and CD8+ specific T-cells was observed after HCV elimination by DAAs therapies. Conclusions Our results show that in chronically infected patients HCV elimination by DAA treatment lead to partial reversion of CD4+ T cell exhaustion. Moreover, proliferative capacity of HCV-specific CD4+ and CD8+ T cells is recovered after DAA’s therapies.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

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Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy

et al. 2021

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“…For example, the use of newer treatments against HCV, consisting of direct-acting antivirals (DDAs), promote a sustained virological response, leading to resolution of the HCV infection. However, although viremia eradication improves liver function, this seems not to be sufficient to completely reverse the cellular profile and production of cytokines, including IL-6, in patients with chronic disease, probably as a result of the change in the structure of the liver parenchyma that makes it impossible to recover homeostasis [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

The IL6-174G/C Polymorphism Associated with High Levels of IL-6 Contributes to HCV Infection, but Is Not Related to HBV Infection, in the Amazon Region of Brazil

Queiroz

Santiago

Moura

et al. 2022

Viruses

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The dysregulation of cytokine production can lead to an inefficient immune response, promoting viral persistence that induces the progression of chronic viral hepatitis. The study investigated the association of the IL6-174G/C polymorphism with changes in cytokine levels and its influence on the persistence and progression of chronic hepatitis caused by HBV and HCV in 72 patients with chronic hepatitis B (HBV), 100 patients with hepatitis C (HCV), and a control group of 300 individuals. The genotyping of the IL6-174G/C polymorphism was performed by real-time PCR, and cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). HCV patients with the wild-type genotype (GG) had a higher viral load (p = 0.0230). The plasma levels of IL-6 were higher among patients infected with HBV and HCV than among the control group (p < 0.0001). Patients with HCV were associated with increased inflammatory activity (A2–A3; p < 0.0001). In hepatitis C, carriers of the GG genotype had higher levels of IL-6 (p = 0.0286), which were associated with A2–A3 inflammatory activity (p = 0.0097). Patients with A2–A3 inflammatory activity and GG genotype had higher levels of IL-6 than those with the GC/CC genotype (p = 0.0127). In conclusion, the wild-type genotype for the IL6 -174G/C polymorphism was associated with high levels of IL-6 and HCV viral load and inflammatory activity, suggesting that this genotype may be a contributing factor to virus-induced chronic infection.

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“…When preexisting drug-resistant substitutions are not a factor, virologic failures to DAA therapy in this group of patients are still a matter of debate. Several factors have been considered as relevant for the success of DAA therapy, including immune reconstitution status, drug user addiction, and the extent of liver damage [ 35 , 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical Relevance of Torque Teno Virus (TTV) in HIV/HCV Coinfected and HCV Monoinfected Patients Treated with Direct-Acting Antiviral Therapy

Lapa

Porto

Minosse

et al. 2021

JCM

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Torque Teno virus (TTV) is a ubiquitous virus that causes chronic infection in humans with unknown clinical consequences. Here, we investigated the influence of TTV infection on HCV direct-acting antiviral (DAA) efficacy in HIV/HCV coinfected and HCV monoinfected patients as controls. Of 92 study patients, 79.3% were TTV DNA positive; untreated patients exhibited a significantly higher proportion of TTV DNA-positivity vs. sustained virological response (SVR) patients (100.0% vs. 65.2%, p < 0.001), while TTV positivity was not significant in DAA failure patients vs. SVR patients despite HIV/HCV coinfection. TTV DNA viral load was higher among HCV monoinfected patients vs. HIV/HCV coinfected, although marginally significant (p = 0.074) and no significant viral load difference was detected between DAA failures and SVR patients, while untreated vs. SVR patients had a significantly higher viral load (19,884, IQR 5977–333,534, vs. 469, IQR 10–4124, p = 0.004). Alpha-genogroup 3 TTV was the most prevalent genetic group, and no specific strain or genogroup was observed in relapser patients. Among HIV/HCV patients with HCV RNA detectable at end of treatment (EOT), TTV DNA was detected in 9/17 treatment responder patients and 3/5 relapser patients, thus, TTV infection does not appear to influence the control HCV viremia after EOT. Levels of IL-6 IL-4, and CD14 were not significantly different between TTV PCR-positive and -negative patients. These results suggest no association between TTV DNA positivity or viral load and HCV DAA failure whether patients were HIV/HCV coinfected or HCV monoinfected.

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Immunological Dynamics Associated with Direct-Acting Antiviral Therapies in Naive and Experimented HCV Chronic-Infected Patients

Cited by 11 publications

References 36 publications

Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy

Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy

The IL6-174G/C Polymorphism Associated with High Levels of IL-6 Contributes to HCV Infection, but Is Not Related to HBV Infection, in the Amazon Region of Brazil

Clinical Relevance of Torque Teno Virus (TTV) in HIV/HCV Coinfected and HCV Monoinfected Patients Treated with Direct-Acting Antiviral Therapy

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