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Signaling Mechanism of HIV-1 gp120 and Virion-Induced IL-1β Release in Primary Human Macrophages¹

Ricky Cheung^*, Vipa Ravyn^*, Lingshu Wang^*, Andrzej Ptasznik and Ronald G. Collman^2,*

^* Pulmonary, Allergy, and Critical Care and Hematology and Oncology Divisions, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

HIV-1 envelope glycoprotein gp120 induces, independently of infection, the release of proinflammatory cytokines, including IL-1β from macrophages, that are implicated in the pathogenesis of HIV-associated dementia. However, the signal transduction pathways involved have not been fully defined. Previously, our laboratory reported that soluble gp120 activates multiple protein kinases in primary human monocyte-derived macrophages, including the Src family kinase Lyn, PI3K, and the focal adhesion-related proline-rich tyrosine kinase Pyk2. In this study we showed that gp120 induces IL-1β release from macrophages in a time- and concentration-dependent manner through binding to the chemokine receptor CCR5 and coupling to G_i protein. Using pharmacological inhibitors and small interfering RNA gene knockdown, we demonstrated that concomitant activation of Lyn, Pyk2, and class IA PI3K are required for gp120-induced IL-1β production. By coimmunoprecipitation and immunofluorescence confocal microscopy, we showed that CCR5 activation by gp120 triggered the assembly of a signaling complex involving endogenous Lyn, PI3K, and Pyk2 and is associated with PI3K and Pyk2 translocation from the cytoplasm to the membrane where they colocalized with Lyn. Finally, we demonstrated that virion-associated gp120 induced similar response, as structurally intact whole virions also triggered IL-1β release and re-localization of PI3K and Pyk2. This study identifies a novel signaling mechanism for HIV-1-induced IL-1β production by primary human macrophages that may be involved in the neuropathogenesis of HIV-associated dementia.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants MH061139, NS027405, AI 35502 (to R.G.C.), and CA108552 (to A.P.). R.C. is the recipient of a Canadian Institutes of Health Research postdoctoral fellowship award.

² Address correspondence and reprint requests to Dr. Ronald G. Collman, Department of Medicine, University of Pennsylvania, 522 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104-6061. E-mail address: collmanr{at}mail.med.upenn.edu

³ Abbreviations used in this paper: HAD, HIV-associated dementia; CaMKII, calcium/calmodulin-dependent protein kinase II; Env, envelope; GPCR, G protein-coupled receptor; GSK3, glycogen synthase kinase 3; MDM, monocyte-derived macrophage; PTX, pertussis toxin; Pyk2, proline-rich tyrosine kinase 2; SFK, Src family kinase; SH, Src homology; siRNA, small interfering RNA.

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