Background

CD56 pos NK/NT cells are important innate effectors providing the first line of defense against viral infection. Enhanced NK activity has been shown to protect from HIV-1 infection. However, the role played by these innate effectors in protection against or development of HCV infection is unknown.

Methods

We characterized CD56 pos populations in 11 intravenous drug users (IDUs) who remained uninfected despite being repeatedly exposed to HCV. NK profiles in exposed uninfected (EU) individuals were compared to pre-infection samples (median 90 days prior to HCV seroconversion) collected from 14 IDUs who subsequently became infected (EI) and unexposed normal control subjects (NC, n= 8).

Results

Flow cytometric analysis of CD56 pos populations demonstrated that EUs had a higher proportion of CD56 low mature (p= 0.0011) NK cells compared to subjects who subsequently became infected. Bead-isolated NKs (> 90% purity) from EUs had significantly higher IL-2 induced cytolytic activity against the NK-sensitive cell line K562 at an effector to target ratio of 10: 1 (p< 0.0001). NKp30, a natural cytotoxicity receptor involved in NK activation, is highest on NK/NT cells in EUs relative to infected subjects. Using the JFH-1 infection system we demonstrate that NKp30 high cells in the absence of exogenous stimulation significantly reduce infection of hepatocytes.

Conclusions

We demonstrate that CD56 pos populations in EUs are enriched for effector NKs displaying enhanced IL-2 induced cytolytic activity and higher levels of NCR NKp30 activating receptor. In addition NKp30 high NK cells are more effective in preventing infection of Huh 7.5 cells than their NKp30 low/neg counterparts. For the first time, these data support the hypothesis that NK cells contribute to anti-HCV defense in vivo in the earliest stages of infection, providing innate protection from HCV acquisition.