Effects of the CCR5-Delta32 mutation on hepatitis C virus-specific immune responses in patients with haemophilia.
In hepatitis C virus (HCV) infection antiviral T cells express the CC chemokine receptor 5 (CCR5). Their recruitment to the liver is an important step in the immune response. A 32 base pair deletion in the CCR5 gene leads to reduced expression and total loss of CCR5 in CCR5-Delta32 heterozygous and homozygous subjects, respectively. However, the role of this mutation for antiviral immunity remains unclear. Here, we analysed proliferation, IFN-gamma and IL-4 secretion (ELISpot) induced by the HCV antigens core, NS3, NS4, and NS5a in 21 anti-HCV-positive haemophiliac patients in relationship to their CCR5 genotypes (CCR5 wildtype n = 10, CCR5-Delta32 heterozygous n = 5 and CCR5-Delta32 homozygous n = 6). Furthermore, T cell migration in response to the CCR5 ligands CCL3, -4 and -5 was studied. Overall IFN-gamma responses to HCV proteins were only slightly greater in CCR5 wild-type patients than in CCR5-Delta32 carriers (0.6 versus 0.24 SFC/10(4) PBMC; p = 0.043). This difference was consistently seen with all tested HCV antigens. In contrast, neither T cell migration, nor PBMC proliferation, nor IL-4 production differed between CCR5 genotypes. Interruption of the CCR5 signalling pathway due to CCR5-Delta32 may potentially result in subtle reduction of HCV specific IFN-gamma responses in anti-HCV-positive haemophiliac patients.
Ahlenstiel
Golo
G
Department of Internal Medicine I, University of Bonn, Bonn, Germany.
Woitas
Rainer P
RP
Iwan
Agathe
A
Nattermann
Jacob
J
Feldmann
Georg
G
Rockstroh
Jürgen K
JK
Oldenburg
Johannes
J
Kupfer
Bernd
B
Sauerbruch
Tilman
T
Spengler
Ulrich
U
D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D006467:Hemophilia A / Q000150:complications* / Q000235:genetics* / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019713:Receptors, CCR5 / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*; D017361:Viral Nonstructural Proteins / Q000276:immunology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
D007371:Interferon-gamma; D015847:Interleukin-4; D019713:Receptors, CCR5; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase