GB Virus C Particles Inhibit T Cell Activation via Envelope E2 Protein-Mediated Inhibition of TCR Signaling

被引:32
作者
Bhattarai, Nirjal [1 ,2 ,3 ]
McLinden, James H. [1 ,3 ]
Xiang, Jinhua [1 ,3 ]
Landay, Alan L. [4 ]
Chivero, Ernest T. [1 ,2 ]
Stapleton, Jack T. [1 ,2 ,3 ,5 ]
机构
[1] Iowa City Vet Affairs Med Ctr, Iowa City, IA 52242 USA
[2] Univ Iowa, Interdisciplinary Program Mol & Cellular Biol, Iowa City, IA 52242 USA
[3] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA
[4] Rush Univ, Med Ctr, Chicago, IL 60612 USA
[5] Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA
基金
美国国家卫生研究院;
关键词
HIV-INFECTED INDIVIDUALS; ANTIRETROVIRAL THERAPY; IMMUNE ACTIVATION; VIRAL LOAD; EXOSOMES; SURVIVAL; VIREMIA; BIND; RNA; REPLICATION;
D O I
10.4049/jimmunol.1300589
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:6351 / 6359
页数:9
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