title: HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFN{gamma} signaling.
abstract: HIV infection remains a worldwide threat. HIV-1 transactivator protein Tat is one of the retroviral proteins identified as a key immunomodulator in AIDS pathogenesis. Although the primary function of Tat is to regulate HIV-1 replication in the infected cell, it also dysregulates cytokine production resulting in perturbation of the host immune response and enhancement of the retrovirus survival. Because interferon-gamma (IFNgamma) is a pleiotropic cytokine with potent antiviral and immunoregulatory effects, we investigated whether Tat interferes with the IFNgamma signal transduction in primary monocytes. We demonstrated that Tat impaired the IFNgamma-receptor signaling pathway at the level of STAT1 activation, possibly via Tat-dependent induction of suppressor of cytokine signaling-2 (SOCS-2) activity. We delineated the inhibitory role of SOCS-2 in IFNgamma signaling pathway by overexpression of exogenous SOCS-2 in HEK293 cell. The results showed that SOCS-2 suppressed the IFNgamma-activated STAT1 phosphorylation and consequent IFNgamma-regulated transcription of specific genes. To confirm the role of SOCS2 in the Tat-induced process, we demonstrated that SOCS-2 siRNA in human blood monocytes abrogated the Tat-dependent inhibition of IFNgamma signaling. Our data suggested a possible mechanism implicating the role of SOCS-2 in mediating HIV-1-induced immune evasion and dysregulation of IFNgamma signaling in primary human monocytes.
authors.affiliation: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Pokfulam, SAR, China.
authors.forename: Sherman M
authors.initials: SM
authors.lastname: Cheng
authors.forename: James C B
authors.initials: JC
authors.lastname: Li
authors.forename: San San
authors.initials: SS
authors.lastname: Lin
authors.forename: Davy C W
authors.initials: DC
authors.lastname: Lee
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Chen
authors.forename: Allan S Y
authors.initials: AS
authors.lastname: Lau
mesh_terms: D002478:Cells, Cultured; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007109:Immunity; D007371:Interferon-gamma / Q000378:metabolism*; D009000:Monocytes / Q000821:virology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*; D015533:Transcriptional Activation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
chemical_list: C106643:SOCS2 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma