title: GB virus C particles inhibit T cell activation via envelope E2 protein-mediated inhibition of TCR signaling.
abstract: Viruses enter into complex interactions within human hosts, leading to facilitation or suppression of each other's replication. Upon coinfection, GB virus C (GBV-C) suppresses HIV-1 replication in vivo and in vitro, and GBV-C coinfection is associated with prolonged survival in HIV-infected people. GBV-C is a lymphotropic virus capable of persistent infection. GBV-C infection is associated with reduced T cell activation in HIV-infected humans, and immune activation is a critical component of HIV disease pathogenesis. We demonstrate that serum GBV-C particles inhibited activation of primary human T cells. T cell activation inhibition was mediated by the envelope glycoprotein E2, because expression of E2 inhibited TCR-mediated activation of Lck. The region on the E2 protein was characterized and revealed a highly conserved peptide motif sufficient to inhibit TCR-mediated signaling. The E2 region contained a predicted Lck substrate site, and substitution of an alanine or histidine for the tyrosine reversed TCR-signaling inhibition. GBV-C E2 protein and a synthetic peptide representing the inhibitory amino acid sequence were phosphorylated by Lck in vitro. The synthetic peptide also inhibited TCR-mediated activation of primary human CD4(+) and CD8(+) T cells. Extracellular microvesicles from GBV-C E2-expressing cells contained E2 protein and inhibited TCR signaling in bystander T cells not expressing E2. Thus, GBV-C reduced global T cell activation via competition between its envelope protein E2 and Lck following TCR engagement. This novel inhibitory mechanism of T cell activation may provide new approaches for HIV and immunoactivation therapy.
authors.affiliation: Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
authors.forename: Nirjal
authors.initials: N
authors.lastname: Bhattarai
authors.forename: James H
authors.initials: JH
authors.lastname: McLinden
authors.forename: Jinhua
authors.initials: J
authors.lastname: Xiang
authors.forename: Alan L
authors.initials: AL
authors.lastname: Landay
authors.forename: Ernest T
authors.initials: ET
authors.lastname: Chivero
authors.forename: Jack T
authors.initials: JT
authors.lastname: Stapleton
mesh_terms: D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D029407:GB virus C / Q000276:immunology* / Q000378:metabolism; D006525:Hepatitis, Viral, Human / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D014759:Viral Envelope Proteins