Hepatitis C virus core protein inhibits human T lymphocyte responses by a complement-dependent regulatory pathway.
Complement proteins are involved in early innate immune responses against pathogens and play a role in clearing circulating viral Ags from the blood of infected hosts. We have previously demonstrated that hepatitis C virus (HCV) core, the first protein to be expressed and circulating in the blood of infected individuals, inhibited human T cell proliferative response through interaction with the complement receptor, globular domain of C1q receptor (gC1qR). To investigate the mechanisms of HCV core/gC1qR-induced inhibition of T cell proliferation, we examined the effect of core protein on the early events in T cell activation. We found that HCV core inhibited phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated ERK kinase (MEK). HCV core-induced impairment of ERK/MEK mitogen-activated protein kinase resulted in the inhibition of IL-2 and IL-2Ralpha gene transcription, which led to the inhibition of IL-2 production and high-affinity IL-2R expression. Importantly, the ability of anti-gC1qR Ab treatment to reverse HCV core-induced inhibition of ERK/MEK phosphorylation reveals that the interaction between HCV core and gC1qR is linked to the interference of ERK/MEK mitogen-activated protein kinase activation. These results imply that HCV core-induced blockage of intracellular events in T cell activation by a complement-dependent regulatory pathway may play a critical role in the establishment of HCV persistence during the acute phase of viral infection.
Yao
Z Q
ZQ
Department of Microbiology and Pathology, Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.
Nguyen
D T
DT
Hiotellis
A I
AI
Hahn
Y S
YS
D002352:Carrier Proteins; D006526:Hepatitis C / Q000276:immunology* / Q000821:virology; D006801:Humans; D018960:Hyaluronan Receptors; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D008213:Lymphocyte Activation; D048728:MAP Kinase Kinase Kinase 1; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011951:Receptors, Complement / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic; D014758:Viral Core Proteins / Q000502:physiology*
C087299:C1QBP protein, human; D002352:Carrier Proteins; D018960:Hyaluronan Receptors; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D011951:Receptors, Complement; D015375:Receptors, Interleukin-2; D014758:Viral Core Proteins; C032402:complement 1q receptor; C069130:nucleocapsid protein, Hepatitis C virus; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human