Submitted October 10, 2008
Accepted February 26, 2009
HIV-1 trans-activator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFN
signaling
Sherman M. Cheng, James C.B. Li, Belinda S.S. Lin, Davy C.W. Lee, Li Liu, Zhiwei Chen, and Allan S.Y. Lau*
Cytokine Biology Group, Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
Bio-Screening Unit, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
AIDS Institute, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
* Corresponding author; email: asylau{at}hku.hk.
Human immunodeficiency virus infection remains a worldwide threat. HIV-1 transactivator protein Tat is one of the retroviral proteins identified as a key immunomodulator in AIDS pathogenesis. While 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. Since Interferon-
is a pleiotropic cytokine with potent antiviral and immunoregulatory effects, we investigated whether Tat interferes with the IFN signal transduction in primary monocytes. We demonstrated that Tat impaired the IFN-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 IFN signaling pathway by overexpression of exogenous SOCS-2 in HEK293 cell. The results showed that SOCS-2 suppressed the IFN-activated STAT1 phosphorylation and consequent IFN 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 IFN signaling. Our data suggested a possible mechanism implicating the role of SOCS-2 in mediating HIV-1-induced immune evasion and dysregulation of IFN signaling in primary human monocytes.
