Abstract
Hepatitis C virus (HCV)-specific CD8+ T cell response is essential in natural HCV infection control, but it becomes exhausted during persistent infection. Nowadays, chronic HCV infection can be resolved by direct acting anti-viral treatment, but there are still some non-responders that could benefit from CD8+ T cell response restoration. To become fully reactive, T cell needs the complete release of T cell receptor (TCR) signalling but, during exhaustion this is blocked by the PD-1 effect on CD28 triggering. The T cell pool sensitive to PD-1 modulation is the progenitor subset but not the terminally differentiated effector population. Nevertheless, the blockade of PD-1/PD-L1 checkpoint cannot be always enough to restore this pool. This is due to the HCV ability to impair other co-stimulatory mechanisms and metabolic pathways and to induce a pro-apoptotic state besides the TCR signalling impairment. In this sense, gamma-chain receptor cytokines involved in memory generation and maintenance, such as low-level IL-2, IL-7, IL-15, and IL-21, might carry out a positive effect on metabolic reprogramming, apoptosis blockade and restoration of co-stimulatory signalling. This review sheds light on the role of combinatory immunotherapeutic strategies to restore a reactive anti-HCV T cell response based on the mixture of PD-1 blocking plus IL-2/IL-7/IL-15/IL-21 treatment.
Highlights
Hepatitis C virus (HCV) is a non-cytopathic, hepatotropic, ssRNA Flaviviridae virus able to induce a chronic hepatitis in 65–85% of infected individuals with around 80 million viraemic population worldwide and, it is the leading cause of liver-related death [1].Nowadays, the natural history of HCV infection has changed due to the discovery of an effective treatment based on direct-acting antivirals (DAA), capable of impairing HCV replicative machinery [2]
This work is a proof of concept of the high immunotherapeutic potential of combining γc-cytokines plus PD-1/PD-L1 pathway blockade to rescue HCV-specific CD8 T cells from exhaustion, but it is necessary to address the role of IL-15 or IL-21 plus anti-PD-1 treatment in HCV infection
This subset is sensitive to PD-1/PD-L1 blockade, but this strategy cannot be enough in most of the cases due to the steady epigenetic changes induced by the exhaustion in different cellular functions, such as mitochondrial metabolism, positive co-stimulation or pro-apoptotic status
Summary
Hepatitis C virus (HCV) is a non-cytopathic, hepatotropic, ssRNA Flaviviridae virus able to induce a chronic hepatitis in 65–85% of infected individuals with around 80 million viraemic population worldwide and, it is the leading cause of liver-related death [1]. The CD8+ T cell differentiation program starts with a stem-cell like subset, called precursor pool that is able of self-renewal and it is in charge of giving rise to the effector progeny [24,25,26]. This specific pool is characterized by the expression of the specific transcription factor T cell factor 1 (TCF-1) and receptors for gamma-chain(γc) cytokines such as interleukin (IL)-7 receptor (R), IL-21R or IL-15R [27,28]. In more progressed disease will be necessary to carry out combination strategies, in which the addition of survivals cytokines could be effective [30,31], and in long-term disease all these approaches would fail due to the probably deletion of these specific CD8+ T cells [32]
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