Table 1.
Summary of different immune cell populations and their fate after antiviral therapy.
| Authors | Type of patient | No. of patients | Treatment(follow up-EOT)Weeks | Main alterations observed upon HCV clearance | |
|---|---|---|---|---|---|
| Soluble immune mediators | |||||
| Carlin et al. (31) | CHC (cirrhotic and non- cirrhotic) | 131 | SOF/RBV (16 or 20) |
Four inflammatory markers were measured, IP-10, MCP-1, MIP-1β, and IL-18, and all decline during therapy but display different dynamics after therapy. MIP-1β and IP-10 displayed significant difference based on treatment outcome. | |
| Hengst et al. (32) | CHC (cirrhotic & NASH) |
53 | SOF/RBV (36) |
IP-10, IL-12 p40, IFN alpha 2a, IL-18, and TRAIL were upregulated in comparison to NASH and healthy controls. The changes in SIM were not fully reversible upon clearance of viral infection. | |
| Debes et al. (33) | CHC & NASH | 13 | SOF/NS5A/PI (+/−RBV) 96 |
Normalization of innate immunity after viral clearance. | |
| Gorin et al. (34) | CHC & AC | 28 | SOF+PI+3D+NS5A/NA(+/−RBV) (36 or 48) |
Rapid restoration of plasma cytokine milieu observed. Macrophage activation marker s CD163 remained elevated. In addition elevated levels for CSCL10 and sCD14 were observed whereas CCL5 and IL-4 remained suppressed. | |
| T cells | |||||
| CD8 | Martin et al. (35) | CHC | 51 | NA+PI +/−RBV (24) |
Specific phenotypic changes were observed on CD8 T cell but expression of CD127 and PD-1 on global CD8 T cells were not altered by therapy. Specific restoration of CD8 T cell proliferation. |
| Weiland et al. (36) | CHC | 24 | NS5A SOF/3D +/− RBV (8–12) |
HCV-specific CD8T cells were analyzed that displayed T cell exhaustion and memory like characteristic both before and after therapy. Only CD127+/PD1+ subset maintained after clearance. The subset characterized by high expression of transcription factor TCF1. | |
| Aregay et al. (37) | CHC | 40 | SOF/PI/3D/NS5A +/−RBV (24) |
Surface expression of co-regulatory receptors on exhausted HCV-specific CD8 T cells remained unaltered. Mitochondrial dysfunction of exhausted HCV-specific CD8 T cells was not restored. HCV-specific CD8 T cells remained functionally impaired after clearance. | |
| CD4 | Smits et al. (38) | CHC | 248 | SOF/PI/3D/NS5A +/−RBV (24) | HCV-specific CD4 T cells skewed towards a follicular T helper cell phenotype maintained after clearance. |
| Tregs | Langhans et al. (39) | CHC | 14 | SOF+PI/NS5A (54) |
Increased frequency and activation status of Tregs that do not normalize even after long term follow-up. |
| γδ T cells | Ravens et al. (40) | CHC & non cirrhotic | 23 | SOF+NS5A (48) |
NGS and flow cytometeric sorting was performed to monitor the peripheral γδ TCR repertoire and their clonal distribution. Overall clonality and complexity of TCR γδ was comparable to healthy. The γδ T cell compartment and their associated TCR repertoires were highly stable at a long term follow up. |
| Ghosh et al. (41) | CHC | 24 | SOF+NS5A/PI (12) |
Peripheral Vγ9Vδ2 γδ T cells showed phenotypic and functional alterations despite cure. CD38 expression in SVR group was not different from healthy but declined at the EOT but relapsers had higher CD38+ frequencies. | |
| MAIT cells | Hengst et al. (42) | CHC | 26 | SOF+ RBV (72) |
MAIT cells present in lower frequencies, circulating MAITs display altered phenotype, impaired in MR1 dependent function. Function and cell frequency not restored after elimination of virus, no correlation with clinical parameters and liver disease. |
| Spaan et al. (43) | CHC | 22 | PI/NS5A (24) SOF/NS5A+/−RBV (24) |
MAIT cell frequencies decreased in all cohorts. No association between the frequency of MAIT cells and ALT level, HCV RNA, and liver fibrosis score. Patients with differential fibrosis stage showed similar MAIT frequencies. | |
| Bolte et al. (44) | CHC | 42 | SOF+NS5A (24) |
Paired liver biopsies and blood samples were studied. MAIT cell frequency was lower in blood and liver compared to healthy. Liver MAIT cells displayed higher activation and cytotoxicity than MAITs from blood. Impaired MR1 dependent cell function. | |
| Cannizzo et al. (45) | HCV/HIV co-infected, IFN non responders, cART treated | 5 | NS5A/PI/SOF/3D +/− RBV (24) |
At baseline diminished total CD3 and CD8 MAITs compared to healthy and no recovery. Longitudinally. MAIT subsets showed higher CD69, PD-1, and granzyme expression but no difference in CD39 and Il-18R and perforin expression. | |
| Natural killer (NK) | |||||
| Serti et al. (46) | CHC | 13 | NS5A/PI (24) |
Post therapy decrease in NK cell activation and a normalization of NK cell cytotoxic effector functions to healthy. Paired liver biopsies showed similar normalization trend. | |
| Spaan et al. (47) | CHC | 12 | NS5A/PI (12) |
NK cell frequencies altered to levels comparable to healthy. NK cell functions (IFNγ and perforin) not modulated. | |
| Strunz et al. (48) | CHC | 35 | SOF/+ RBV (96) |
NK cells from patients with chronic HCV maintained their functional capacity. Chronic infection reduced NK cell diversity and this reduction persisted long after viral clearance. | |
| Wang et al. (49) | CHC | 26 | SOF/NS5A (24 or 36) |
Significant decline in CD56bright NK cell frequencies that normalize after EOT but no difference in CD56dim NK cells observed. Expression levels of NKG2A, NKp30, and CD94 were high at baseline but recovered to levels those of healthy after EOT. | |
| Jiang et al. (50) | CHC | 13 | SOF/NS5A (24 or 36) |
Expression of functional markers were downregulated after treatment but the potential activity of NK cells gets upregulated. Amongst the NK markers, NKp46 normalized at EOT. | |
| Golden-Mason et al. (51) | Prospective cohort | 22 | LDV/SOF (24) |
Transient activation followed by dampening of NK cell activity to pre- treatment levels | |
| Mele et al. (52) | CHC | 59 | DAA (24) |
Restoration of normal adaptive NK phenotype (activation markers normalized) and restored ADCC ability. | |
CHC, chronic hepatitis C; NASH, non-alcoholic steatohepatitis; AC, alcoholic cirrhotic; SOF, sofosbovir; RBV, ribavirin; PI, Protease inhibitor; NA, nucleot(s)ide analogs; 3D-Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir; EOT, end of treatment; NK, natural killer cells; MAIT, mucosal associated invariant T cells; TCF1, transcription factor; cART, combination antiretroviral therapy.