Protection against hepatitis C infection via NK cells in highly-exposed uninfected injecting drug users.
OBJECTIVE
HCV seroprevalence surveys in longstanding injecting drug users (IDUs) reveal a small minority who remain seronegative, with some exhibiting HCV-specific cellular immunity. This study aimed to characterise this immunity, assess associations with risk behaviours and protection against infection.


METHODS
A nested case-control series from a prospective cohort of seronegative IDUs was selected with incident cases (IN; n = 28) matched by demographics and risk behaviour to exposed uninfected (EU) subjects (n = 28). Samples were assayed for natural killer (NK) cell phenotypes and function, HCV-specific IFNγ in ELISpot, and HCV-specific CD4 T effector responses. IL28B and HLA-C/KIR2DL3 genotypes were tested.


RESULTS
Numbers of activated (CD69(+)) NK cells in the mature CD56(dim)CD16(+) subset, and cytotoxic (NKp30(+)) cells in the CD56(bright)CD16(+) subset were higher in the EU subjects (p = 0.040, p = 0.038 respectively). EU subjects had higher frequencies of interferon gamma (IFNγ) producing NK cells, and lower frequencies of CD107a expression (p = 0.003, p = 0.015 respectively). By contrast, the frequency, magnitude, and breadth of HCV-specific CD4 and CD8 T cell responses did not differ, nor did IL28B, HLA-C, or KIR2DL3 allele frequencies.


CONCLUSIONS
Sustained NK cell activation contributes to protection against HCV infection. HCV-specific cellular immunity is prevalent in EU subjects but does not appear to be protective.
Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia.
Peter B
PB
Sugden
Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia. Electronic address: b.cameron@unsw.edu.au.
Barbara
B
Cameron
Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia.
Michael
M
Mina
Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia.
Andrew R
AR
Lloyd
D000328:Adult; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D055030:Drug Users / Q000523:psychology; D005260:Female; D020869:Gene Expression Profiling; D006526:Hepatitis C / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000276:immunology; D054344:Receptors, KIR2DL3 / Q000235:genetics / Q000276:immunology; D012309:Risk-Taking; D015819:Substance Abuse, Intravenous / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000523:psychology; D000099192:CD69 Antigens; D000095022:Interferon Lambda
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D007372:Interferons; D007378:Interleukins; D037181:Lectins, C-Type; D055628:Natural Cytotoxicity Triggering Receptor 3; D054344:Receptors, KIR2DL3; D000099192:CD69 Antigens; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C515078:KIR2DL3 protein, human
CD4 T cells; CD8 T cells; Exposed uninfected; Genetics; Natural killer cells; Protective immunity