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124 CCR6 Ligands Inhibit HIV in Highly Susceptible CD4+CCR6+ T Cells by Inducing APOBEC3G Expression

Lafferty, Mark K; Sun, Lingling; DeMasi, Leon; Lu, Wuyuan; Garzino-Demo, Alfredo

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 50
doi: 10.1097/01.qai.0000397312.17213.f4

Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD

CD4+CCR6+ T cells are highly susceptible to infection by both R5 and X4 isolates of HIV, as compared to CD4+CCR6- cells. We had shown that two CCR6 ligands (hBD2 and hBD3) inhibit HIV infection. We hypothesized that CCR6 mediates a novel type of antiretroviral activity.

We observed that treatment with CCR6 ligands hBD2, -3, and MIP3α resulted in HIV inhibition and decreased abundance of early products of reverse transcription, which are abrogated by treating cells with PTx, an inhibitor of Gi proteins that are associated to signal transduction mediated by chemokine receptors. We found that expression of the cellular protein APOBEC3G is increased concomitantly with treatment with CCR6 ligands and with decrement of early reverse transcription products. Treatment of cells with a specific siRNA targeting APOBEC3G abrogates HIV inhibition, demonstrating the central role of APOBEC3G in the effects of CCR6 ligands. Induction of APOBEC3G by CCR6 ligands is also abrogated by treatment with pertussis toxin, indicating the requirement of intracellular signaling in this effect. We found that expression of CCR6 ligands is lower in HIV infected subjects than in controls.

Our findings show that CCR6-induced antiviral activity can be a target for novel approaches to treatment and prevention of HIV infection, since CCR6 is expressed on cells most relevant to HIV infection, including CD4+CCR5+ memory T cells, Th17 cells, DC, and activated macrophages.

Copyright © 2011 Wolters Kluwer Health, Inc. All rights reserved.