Direct-Acting Antivirals Cure Innate Immunity in Chronic Hepatitis C.

or a number of years, immunologists have strived to Funderstand the mechanisms associated with treatment-induced eradication of hepatitis C virus (HCV). However, interferon (IFN)-a–based therapies did not allow studies examining the role of the virus itself on innate and adaptive immunity to HCV. The study by Serti et al published in this issue of Gastroenterology provides a unique opportunity to assess the effect of virus on innate immunity, particularly natural killer (NK) cells, which were previously described by the same authors and other groups to be dysfunctional in this setting (reviewed by Golden-Mason and Rosen). HCV is characterized by a high propensity to persist owing to its remarkable skills to evade the host’s innate and adaptive immune responses in complicity with permissive intrahepatic microenvironment, which panders to virus replication while limiting immunopathology. However, the available direct-acting antivirals (DAAs) have highlighted the vulnerability of HCV that, despite sophisticated countermeasures against host immune surveillance, can now be eradicated within weeks of treatment in most cases, whereas the chances of achieving success were significantly lower with the historical pegylated IFN-a/ribavirin combination therapy. The outcome of the latter was uncertain, even accounting for the strongest predictors such as IFN-l3 polymorphism and viral genotype. Therefore, several investigators sought possible pretreatment and treatment immunologic variables associated with success or failure. Importantly, those early studies clearly showed that T cells did not play a lead role in viral eradication, because no HCVspecific T-cell changes were observed in patients who did or did not achieve an early virologic response, and the overall vigor of the HCV-specific T-cell response decreased during treatment. The negative findings on T-cell responses prompted a proliferation of studies on NK cells in the context of hepatitis C treatment, particularly because early work on intrahepatic NK cells isolated from liver explants suggested that innate lymphoid cells were highly prevalent in the liver and constituted about one-half of intrahepatic lymphocytes. Moreover, IFN-a is a potent activator of NK cells, thus providing a strong rationale for investigating their role in treatment responses. Two papers from the authors of the present study pointed to the importance of IFN-a–induced early NK cell activation and type I IFN signaling as a paradigm of response to therapy. Others added further variables associated with responses to IFNa–based therapies while confirming NK activation as a key factor associated with sustained virologic response (SVR). In chronic HCV infection, NK cells are already activated before any exogenous IFN, and are polarized toward cytotoxicity with deficient IFN-g secretion as a consequence of chronic exposure to endogenous IFN-a. This phenomenon is caused by type I IFN-induced phosphorylation of signal transducer and activation of transcription (STAT) 1, which displaces STAT4 at the IFN-a/b receptor resulting in decreased pSTAT4-dependent IFN-g production and increased pSTAT1-dependent cytotoxicity (Figure 1). The net result is a “functional dichotomy” characterized by enhanced NK cytolytic activity and a simultaneous failure to produce adequate amounts of IFN-g and tumor necrosis factor (TNF)-a, with consequent inability to eradicate HCV. It follows that IFN-a–based therapies can only accentuate the NK cell functional dichotomy as a result of massive exposure to exogenous IFN-a. Indeed, as a consequence of STAT1 activation, IFN-g production decreases early in treatment and does not recover for several weeks after IFNa therapy. Whether IFN-g production is actually restored to normal values after SVR is not known, because the study did not have sufficient follow-up to answer this question. After SVR, one would expect a complete reconstitution of immune cell function. Instead, there is evidence that T-cell function remains profoundly altered in most cases after successful IFN-a/ribavirin therapy with T-cell hyporesponsiveness to exogenous stimulation persisting for a long time after virus control, probably as a result of prolonged exposure to viral antigens and consequent exhaustion. A hierarchy of residual HCV-specific T-cell dysfunction was demonstrated with cytotoxicity and IL-2 production being mostly affected. Whether such T-cell functional defects are relevant clinically is unclear presently, although they have the potential to impinge on the efficiency of protection upon reexposure to HCV. NK cell dysfunction is probably not as pervasive, but NK cell efficiency would be highly desirable, being an essential component of the innate/adaptive immunity cross-talk.