The hepatitis C envelope 2 protein inhibits LFA-1-transduced protein kinase C signaling for T-lymphocyte migration.
OBJECTIVE
The ability of viruses to escape the host immune response represents a globally important problem related to a wide variety of pathogens. Hepatitis C is one of the major causes of liver disease worldwide. Clearance rates of this virus are low, and this condition normally involves a chronic inflammatory process. This raises a possibility that the virus may have developed mechanisms enabling it to evade T-cell-mediated immune surveillance. The aim of this study was to investigate the effect of the hepatitis C envelope protein E2 on LFA-1-stimulated T-cell migration and macrophage inflammatory protein (MIP-1alpha, MIP-1beta) secretion.


METHODS
T cells were stimulated through the leukocyte function-associated molecule-1 (LFA-1) receptor by incubating with either intracellular adhesion molecule 1 (ICAM-1)-Fc fusion protein or anti-LFA-1 immobilized on 8-well chamber slides. Subcellular localization of protein kinase C (PKC)-beta, CD81, and LFA-1 was determined by immunofluorescence analysis. Lipid raft formation was assessed using the Cellomics Kineticscan reader. MIP-1alpha and MIP-1beta levels were detected by enzyme-linked immunosorbent assay.


RESULTS
We report that the hepatitis C envelope protein E2 can dramatically inhibit T-lymphocyte motility and chemokine release induced via LFA-1 integrin ligation. We have demonstrated a novel T-lymphocyte-directed viral inhibitory mechanism involving the PKC-beta enzyme as a definitive intracellular target. E2-CD81 interaction stimulates translocation of PKC-beta to lipid rafts, thereby preventing its association with the centrosome and microtubule cytoskeleton, which is crucial to the process of T-cell migration.


CONCLUSIONS
These studies identify a mechanism whereby the hepatitis C virus can evade the host immune response by inhibition of T-cell migration.
Dublin Molecular Medicine Centre and Department of Clinical Medicine, Trinity Centre College, Ireland. yvolkov@tcd.ie
Yuri
Y
Volkov
Aideen
A
Long
Michael
M
Freeley
Lucy
L
Golden-Mason
Cliona
C
O'Farrelly
Anne
A
Murphy
Dermot
D
Kelleher
D002465:Cell Movement; D018925:Chemokines / Q000378:metabolism; D016174:Hepacivirus; D006801:Humans; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000494:pharmacology*; D021962:Membrane Microdomains / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014759:Viral Envelope Proteins / Q000494:pharmacology*
D018925:Chemokines; D016169:Lymphocyte Function-Associated Antigen-1; D014759:Viral Envelope Proteins; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D013755:Tetradecanoylphorbol Acetate