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 Blood, 21 May 2009, Vol. 113, No. 21, pp. 5192-5201.
Prepublished online as a Blood First Edition Paper on March 23, 2009; DOI 10.1182/blood-2008-10-183525.

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IMMUNOBIOLOGY

HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFN{gamma} signaling

Sherman M. Cheng1,*, James C. B. Li1,2,*, San San Lin1, Davy C. W. Lee1, Li Liu3, Zhiwei Chen3, and Allan S. Y. Lau1

1 Cytokine Biology Group, Department of Paediatrics and Adolescent Medicine, 2 Bio-Screening Unit, and 3 AIDS Institute, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China

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} (IFN{gamma}) is a pleiotropic cytokine with potent antiviral and immunoregulatory effects, we investigated whether Tat interferes with the IFN{gamma} signal transduction in primary monocytes. We demonstrated that Tat impaired the IFN{gamma}-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{gamma} signaling pathway by overexpression of exogenous SOCS-2 in HEK293 cell. The results showed that SOCS-2 suppressed the IFN{gamma}-activated STAT1 phosphorylation and consequent IFN{gamma}-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{gamma} signaling. Our data suggested a possible mechanism implicating the role of SOCS-2 in mediating HIV-1–induced immune evasion and dysregulation of IFN{gamma} signaling in primary human monocytes.


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