According to Hepatitis C Virus (HCV) Infection Stage, Interleukin-7 Plus 4-1BB Triggering Alone or Combined with PD-1 Blockade Increases TRAF1 ^low HCV-Specific CD8 ⁺ Cell Reactivity

Abstract

Hepatitis C virus (HCV)-specific CD8 T cells suffer a progressive exhaustion during persistent infection (PI) with HCV. This process could involve the positive immune checkpoint 4-1BB/4-1BBL through the loss of its signal transducer, TRAF1. To address this issue, peripheral HCV-specific CD8 T cells (pentamer-positive [pentamer]/CD8 T cells) from patients with PI and resolved infection (RI) after treatment were studied. The duration of HCV infection and the liver fibrosis progression rate inversely correlated with the likelihood of detection of peripheral pentamer/CD8 cells. In PI, pentamer/CD8 cells had impaired antigen-specific reactivity that worsened when these cells were not detectable Short/midduration PI was characterized by detectable peripheral PD-1 CD127 TRAF1 cells. After triggering of T cell receptors (TCR), the TRAF1 level positively correlated with the levels of CD127, Mcl-1, and CD107a expression and proliferation intensity but negatively with PD-1 expression, linking TRAF1 to exhaustion. treatment with interleukin-7 (IL-7) upregulated TRAF1 expression, while treatment with transforming growth factor-β1 (TGF-β1) did the opposite, suggesting that the IL-7/TGF-β1 balance, besides TCR stimulation, could be involved in TRAF1 regulation. In fact, the serum TGF-β1 concentration was higher in patients with PI than in patients with RI, and it negatively correlated with TRAF1 expression. In line with IL-7 increasing the level of TRAF1 expression, IL-7 plus 4-1BBL treatment enhanced T cell reactivity in patients with short/midduration infection. However, in patients with long-lasting PI, anti-PD-L1, in addition to the combination of IL-7 and 4-1BBL, was necessary to reestablish T cell proliferation in individuals with slowly progressing liver fibrosis (slow fibrosers) but had no effect in rapid fibrosers. In conclusion, a peripheral hyporeactive TRAF1 HCV-specific CD8 T cell response, restorable by IL-7 plus 4-1BBL treatment, characterizes short/midduration PI. In long-lasting disease, HCV-specific CD8 T cells are rarely detectable , but treatment with IL-7, 4-1BBL, and anti-PD-L1 recovers their reactivity in slow fibrosers. Hepatitis C virus (HCV) infects 71 million people worldwide. Two-thirds develop a chronic disease that can lead to cirrhosis and hepatocellular carcinoma. Direct-acting antivirals clear the infection, but there are still patients who relapse. In these cases, additional immunotherapy could play a vital role. A successful anti-HCV immune response depends on virus-specific CD8 T cells. During chronic infection, these cells are functionally impaired, which could be due to the failure of costimulation. This study describes exhausted specific T cells, characterized by low levels of expression of the signal transducer TRAF1 of the positive costimulatory pathway 4-1BB/4-1BBL. IL-7 upregulated TRAF1 expression and improved T cell reactivity in patients with short/midduration disease, while in patients with long-lasting infection, it was also necessary to block the negative PD-1/PD-L1 checkpoint. W...

TRAF1 Signaling in Human Health and Disease

“…Moreover, the authors showed that IL-7 plus 4-1BBL treatment ex vivo could improve T cell responses of chronically infected patients. In a subset of patients, characterized by slowly progressing liver fibrosis, in vitro treatment with anti-PD-L1, in addition to the combination of IL-7 and 4-1BBL, re-established T cell proliferation in individuals with long-lasting persistent infection, once again supporting the idea that TRAF1 is a key regulator involved in supporting specific CD8 + T cell responses during chronic viral infection (90).…”

“…Hepatitis C infection of humans can result in diverse outcomes, from full resolution of infection to long-term chronic infection, which can ultimately lead to liver cirrhosis or hepatocarcinoma. Moreno-Cubero et al recently examined Hepatitis C virus (HCV)-specific CD8 + T cells from patients with progressive infection and those with resolved infection (90). As with chronic HIV infection, progressive exhaustion during persistent infection with HCV was also associated with loss of TRAF1 measured directly ex vivo or after in vitro TCR stimulation.…”

Is it possible to stop nucleos(t)ide analogue treatment in chronic hepatitis B patients?

“…In the setting of acute infection, PD-1 up-regulation is transient, returning to low levels after viral clearance. However, in chronic infection, PD-1 up-regulation is sustained, and the blockade of PD-1/PD-L1 interaction has shown promising results in restoring virus-specific T cell functionality[ 80 - 83 ]. Therefore, a PD-1+ phenotype could mean both activation before clearance or exhaustion after persistent and high antigenemia.…”

T cell metabolism in chronic viral infection

“…Statins that inhibit cholesterol synthesis have an inhibitory effect on the replication of several different viruses in vitro, including HCV REVIEW SERIES: TRANSLATING IMMUNOMETABOLISM [87] and CMV [88], while blockade of CD36 on macrophages inhibits the release, and therefore transmission, of HIV-1 particles [89]. IL-7, IL-12 [40,90]), or the modulation of mitochondrial biogenesis (e.g. The supplementation of amino acids (e.g.…”

“…arginine [41]) or cytokines (e.g. IL-7, IL-12 [40,90]), or the modulation of mitochondrial biogenesis (e.g. via an enhanced expression of PPARγ co-activator1α [67]) with or without checkpoint inhibition, are all promising targets to improve in vivo survival and effector function of transferred antiviral T cells.…”