HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFN{gamma} signaling.
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.
Cheng
Sherman M
SM
Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Pokfulam, SAR, China.
Li
James C B
JC
Lin
San San
SS
Lee
Davy C W
DC
Liu
Li
L
Chen
Zhiwei
Z
Lau
Allan S Y
AS
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*
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