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Transforming growth factor-beta1 increases CXCR4 expression, stromal-derived factor-1alpha-stimulated signalling and human immunodeficiency virus-1 entry in human monocyte-derived macrophages.

Shuzhen Chen·Daniel L Tuttle·Joseph T Oshier·Harm J Knot·Wolfgang J Streit·Maureen M Goodenow·Jeffrey K Harrison
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Abstract

Stromal-derived factor-1 (SDF-1/CXCL12) and its receptor CXCR4 play crucial roles in leukocyte migration and activation, as well as embryogenesis, angiogenesis, cancer and viral pathogenesis. CXCR4 is one of the major human immunodeficiency virus-1 (HIV-1) coreceptors on macrophages. In many tissues macrophages are one of the predominant cell types infected by HIV-1 and act as a reservoir for persistent infection and viral dissemination. In patients infected by HIV-1, blood and tissue levels of transforming growth factor-beta1 (TGF-beta1) are increased. The purpose of this study was to evaluate the effects of TGF-beta1 on CXCR4 expression and function in primary human monocyte-derived macrophages (MDMs) and rat microglia. TGF-beta1 up-regulated CXCR4 and enhanced SDF-1alpha-stimulated ERK1,2 phosphorylation in these cells. The increased CXCR4 expression in human MDMs resulted in increased susceptibility of the cells to entry by dual-tropic CXCR4-using HIV-1 (D-X4). In contrast, TGF-beta1 failed to increase CCR5 expression or infection by a CCR5-using virus in MDMs. Our data demonstrate that TGF-beta1 enhances macrophage responsiveness to SDF-1alpha stimulation and susceptibility to HIV-1 by selectively increasing expression of CXCR4. The results suggest that increased expression of CXCR4 on macrophages may contribute to the emergence of dual-tropic X4 viral variants at later stages of HIV-1 infection.

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AnimalsCells, CulturedChemokine CXCL12Chemokines, CXCExtracellular Signal-Regulated MAP KinasesFlow CytometryHIV InfectionsHIV-1HumansMacrophagesMicrogliaMicroscopy, FluorescencePhosphorylationRatsReceptors, CXCR4Receptors, ChemokineTransforming Growth Factor betaJournal ArticleResearch Support, U.S. Gov't, P.H.S.

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Shuzhen Chen, Daniel L Tuttle, Joseph T Oshier, Harm J Knot, Wolfgang J Streit, Maureen M Goodenow, Jeffrey K Harrison. 2005. Transforming growth factor-beta1 increases CXCR4 expression, stromal-derived factor-1alpha-stimulated signalling and human immunodeficiency virus-1 entry in human monocyte-derived macrophages.. https://doi.org/10.1111/j.1365-2567.2004.02110.x

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