In patients with the favorable IL28B genotype, IP-10 levels tended to be lower but correlated well with the level of HCV RNA, suggesting that in this setting IP-10 production, and possibly production of other ISGs, is driven by and thus proportionate to the amount of virus present. However, in patients with the unfavorable genotypes IP-10 Selleck NVP-LDE225 levels were on average higher and appeared to be entirely independent of the HCV RNA level. This might suggest that the fundamental problem in those with the unfavorable genotypes is a loss of regulation of ISG induction such that ISGs are produced independent of the stimulus and therefore lead

to a less coordinated viral response. Although speculative, further research on this relationship could help clarify the elusive role of the IL28B genotype.

Although IP-10 is an ISG, it is also an important chemotactic factor for cells of the adaptive immune response, which are very important for spontaneous clearance. Higher levels of IP-10 might be expected to drive more immune cells to the liver and thus promote viral clearance. However, recent evidence has shown that IP-10 can undergo cleavage to form an inactive version of the protein that may act as a dominant negative by binding the CXCR3 receptor without leading to chemotaxis.19 It is possible that the higher levels of IP-10 seen in patients without spontaneous clearance are due to the cleaved inactive form of IP-10. Lastly, an additional explanation is that very high IP-10 levels may lead Rucaparib solubility dmso to chemorepulsion inhibiting migration of

immune cells to the liver, leading to persistent HCV infection. Understanding the role of IP-10 cleavage in HCV and other infections is clearly a priority for future studies. The observation that individuals of Aboriginal ethnicity had a lower proportion with high plasma IP-10 levels compared to Caucasians is unexpected and notably independent of IL28B genotype. Black ethnicity has been associated with higher IP-1017, 24 and preactivated ISG expression profiles10 compared to Caucasians, which has been attributed to SNPs in interferon Selleck Afatinib signaling pathway genes and interferon-stimulated genes, but is not completely understood.11 Further research investigating the role of Aboriginal ethnicity and IP-10 levels would be interesting to clarify whether there are pathways for differential innate immune responses that might lead to lower IP-10 production and ultimately explain the higher rates of spontaneous clearance reported in Aboriginals.29 As previously reported in chronic HCV, associations between plasma IP-10 levels and IL28B genotype18, 25 and HCV genotype16, 26 were observed in unadjusted analyses, but these were not significant in adjusted analysis. An association was observed between higher ALT and IP-10 levels in acute HCV, which is consistent with previous data in chronic HCV.