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Molecular mechanism(s) involved in the synergistic induction of CXCL10 by human immunodeficiency virus type 1 Tat and interferon-γ in macrophages

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An Erratum to this article was published on 01 March 2009

Abstract

Synergistic interactions between viral proteins and soluble host factors released from infected mononuclear phagocytes play a critical role in the pathogenesis of human immunodeficiency virus (HIV)-associated dementia (HAD). The chemokine CXCL10 has been found to be closely associated with the progression of HIV-1-related central nervous system (CNS) disease and its related neuropsychiatric impairment. In this report the authors demonstrate that the HIV-1 protein Tat can interact with the proinflammatory cytokine interferon (IFN)-γ to dramatically induce the expression of CXCL10 in macrophages. Synergistic induction of CXCL10 by both Tat and IFN-γ was susceptible to inhibition by the MEK1/2 inhibitor U0126 and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. In addition, JAK/STAT pathway plays a major role in Tat/γ-mediated CXCL10 induction in macrophages because pre-treatment of stimulated macrophages with JAK inhibitor completely abrogated the synergistic induction of the chemokine. Functionality of the synergistically induced CXCL10 was further demonstrated by its chemotactic activity for peripheral blood lymphocytes. Taken together, these findings demonstrate that the cooperative interaction of Tat and IFN-γ results in enhanced chemokine expression, which in turn can amplify the inflammatory responses within the CNS of HAD patients by recruiting more lymphocytes in the brain.

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Authors and Affiliations

  1. Department of Molecular and Integrative Physiology, 5000 Wahl Hall East, University of Kansas Medical Center, 3901 Rainbow Boulevard, 66160, Kansas City, KS, USA

    Navneet Dhillon, Xuhui Zhu, Fuwang Peng, Honghong Yao, Rachel Williams, Shannon Callen & Shilpa Buch

  2. Department of Pulmonary and Critical Care Medicines, University of Kansas Medical Center, Kansas City, Kansas, USA

    Amy O’Brien Ladner

  3. Department of Microbiology, University of Kansas Medical Center, Kansas City, Kansas, USA

    Jianming Qiu

Authors
  1. Navneet Dhillon
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  2. Xuhui Zhu
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  3. Fuwang Peng
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  4. Honghong Yao
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  5. Rachel Williams
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  6. Shannon Callen
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  7. Amy O’Brien Ladner
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  8. Shilpa Buch
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  9. Jianming Qiu
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Corresponding author

Correspondence to Shilpa Buch.

Additional information

Navneet Dhillon and Xuhui Zhu contributed equally to the study.

This work was supported by grants MH62969-01, RR016443, MH-068212, MH072355, and DA020392-01 from the National Institutes of Health and a fellowship from Parker B. Francis foundation.

An erratum to this article is available at http://dx.doi.org/10.1080/13550280902827067.

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Dhillon, N., Zhu, X., Peng, F. et al. Molecular mechanism(s) involved in the synergistic induction of CXCL10 by human immunodeficiency virus type 1 Tat and interferon-γ in macrophages. Journal of NeuroVirology 14, 196–204 (2008). https://doi.org/10.1080/13550280801993648

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