Direct-acting antivirals trump interferon-alpha in their capacity to rescue exhausted T cells upon HCV clearance

Abstract

The treatment of HCV has been transformed by the capacity of direct acting antivirals (DAAs) to eliminate the infection by attacking the virus effectively. In this issue Martin et al. reveal that these drugs can also harness the immune system by releasing it from the burden of chronic antigen load [1]. Their important findings underscore a detrimental immunoregulatory component to the effects of interferon-alpha (IFN-a), which was not able to boost antiviral T cells in the manner now demonstrated with DAAs, even when it achieved viral clearance (Fig. 1). CD8 T cells are well-recognised to be critical for the control of viruses such as HCV but to be depleted and dysfunctional (exhausted) in chronic infection [2–5]. There are clear demonstrations of the inverse relationship between duration and level of viraemia and T cell responses in murine and human persistent viral infections [2,3,6]. However it has been difficult to determine to what extent the persistent, high antigen load in these settings contributes to the failure of the T cell response [7] or is rather a result of it. A vital issue in the attempt to cure persistent viral infection is whether removal of antigen will be sufficient to allow recovery of T cells with antiviral efficacy. Alternatively, T cells may be permanently scarred by, for example, stable imprinting of PD-1 [8], or subject to other ongoing tolerising mechanisms, which are particularly prevalent in the liver environment [9]. Previous data from the HCV field had suggested that whilst T cells show variable recovery following spontaneous or therapeutic removal of antigen in acute infection, they might no longer be amenable to rescue in chronic infection [4,10,11]. Thus patients with IFN-a induced clearance of chronic HCV had no consistent recovery of virus-specific T cells [10–12]. Now the Thimme group demonstrate that when the antigen load is reduced by IFN-free therapy, there is a striking recovery of the capacity of HCV-specific T cells to expand in culture. Responders to DAAs had a significant increase in the number of detectable HCV-specific responses, and in their frequencies after in vitro expansion,