Cytokine profiles in high risk injection drug users suggests innate as opposed to adaptive immunity in apparent resistance to hepatitis C virus infection

Abstract

A cohort of injection drug users (IDU) have been identified who despite a long history of IDU and sharing of injecting equipment remain seronegative and aviraemic for hepatitis C virus (HCV). They have been termed HCV exposed uninfected (EU). The study of potential innate or adaptive immune mechanisms of resistance to HCV infection in this group is of interest. The aim of this study was to determine the levels of a broad range of cytokines in serum of exposed, uninfected individuals to ascertain whether there is a specific cytokine profile associated with apparent resistance to HCV. Sera from 22 EU individuals were analysed for a range of cytokines and chemokines, and compared to 16 treatment-naive chronic HCV cases (HCV Ab+ RNA+), 16 individuals with spontaneous resolution of HCV (HCV-Ab+ and HCV-RNA-) and 10 healthy unexposed controls. EU subjects had strikingly higher levels of both IL-6 (on average more than 100-fold, P = 0.001) and IL-8 (on average more than 10-fold, P < 0.001) than the comparison groups. Additionally higher levels of tumour necrosis factor-alpha (TNF-α; on average up to threefold, P = 0.02) were seen in EU individuals. The levels of interferon-alpha (IFN-α) were upregulated in all HCV exposed groups in comparison to healthy controls (P = 0.013). Adaptive immune cytokine levels were no different between the groups. Cytokine profiling demonstrated raised levels of pro-inflammatory innate immune cytokines and chemokines in EU IDU, in particular interleukin-6 and interleukin-8. These findings suggest innate immune activation may be the key to prevention of infection in this cohort.

Synergism of Tapasin And Human Leukocyte Antigens in Resolving Hepatitis C Virus Infection

“…To confirm that this effect was indeed population‐specific, we typed a further UK cohort of 75 individuals at high risk of HCV infection due to multiple episodes of intravenous drug use but who remained seronegative and aviremic. These individuals have detectable T‐cell responses, a protective KIR:HLA‐C type, and distinct serum cytokine profile, consistent with exposure to HCV infection . As a comparator group we typed a further 79 individuals from the UK with chronic HCV infection.…”

In vitro infection of primary human hepatocytes by HCV-positive sera: insights on a highly relevant model

“…In vitro, IL-8 can inhibit IFN-α activity,37 but IL-8 upregulation by ribavirin might participate in enhancing IFNα antiviral effects 38. It has been also recently proposed that high IL-8 serum levels might protect injection drug users from HCV infection 39. Finally, ENA-78 and IL-8 are mitogenic in rat hepatocytes,40 suggesting that these cytokines could also act on human hepatic parenchymal cells.…”

Exploration of potential mechanisms of hepatitis C virus resistance in exposed uninfected intravenous drug users

“…There is increasing evidence to support a key role for innate immune responses in EU cases. A study looking at serum cytokine profiles in EU cases found significantly elevated levels of the pro‐inflammatory innate immune cytokine interleukin‐6 and chemokine interleukin‐8 in EUs compared to those with chronic HCV, spontaneous resolvers or healthy controls . A genetic study of the NK‐cell KIR receptors identified homozygosity for KIR2DL3:HLA‐C1, which is linked to a readily activated NK‐cell phenotype, to be associated with the resistance to HCV infection seen in EU cases .…”