Direct binding of hepatitis C virus core to gC1qR on CD4+ and CD8+ T cells leads to impaired activation of Lck and Akt.
Complement plays a pivotal role in the regulation of innate and adaptive immunity. It has been shown that the binding of C1q, a natural ligand of gC1qR, on T cells inhibits their proliferation. Here, we demonstrate that direct binding of the hepatitis C virus (HCV) core to gC1qR on T cells leads to impaired Lck/Akt activation and T-cell function. The HCV core associates with the surface of T cells specifically via gC1qR, as this binding is inhibited by the addition of either anti-gC1qR antibody or soluble gC1qR. The binding affinity constant of core protein for gC1qR, as determined by BIAcore analysis, is 3.8 x 10(-7) M. The specificity of the HCV core-gC1qR interaction is confirmed by reduced core binding on Molt-4 T cells treated with gC1qR-silencing small interfering RNA and enhanced core binding on GPC-16 guinea pig cells transfected with human gC1qR. Interestingly, gC1qR is expressed at higher levels on CD8(+) than on CD4(+) T cells, resulting in more severe core-induced suppression of the CD8(+)-T-cell population. Importantly, T-cell receptor-mediated activation of the Src kinases Lck and ZAP-70 but not Fyn and the phosphorylation of Akt are impaired by the HCV core, suggesting that it inhibits the very early events of T-cell activation.
Yao
Zhi Qiang
ZQ
Department of Microbiology and Beirne Carter Center, University of Virginia, HSC Box 801386, Charlottesville, VA 22908, USA.
Eisen-Vandervelde
Audrey
A
Waggoner
Stephen N
SN
Cale
Evan M
EM
Hahn
Young S
YS
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D002352:Carrier Proteins; D002460:Cell Line; D006168:Guinea Pigs; D016174:Hepacivirus / Q000472:pathogenicity*; D006801:Humans; D018960:Hyaluronan Receptors; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011951:Receptors, Complement / Q000378:metabolism*; D014162:Transfection; D014758:Viral Core Proteins / Q000378:metabolism*
C087299:C1QBP protein, human; D002352:Carrier Proteins; D018960:Hyaluronan Receptors; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D011951:Receptors, Complement; D014758:Viral Core Proteins; C032402:complement 1q receptor; C069130:nucleocapsid protein, Hepatitis C virus; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt