Human Beta Defensin 2 Selectively Inhibits HIV-1 in Highly Permissive CCR6⁺CD4⁺ T Cells.

Mark Lafferty,Alfredo Garzino-Demo,Lingling Sun,Aaron Christensen-Quick,Wuyuan Lu

doi:10.3390/v9050111

Mark Lafferty, Alfredo Garzino-Demo + Show 3 more

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https://doi.org/10.3390/v9050111

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Journal: Viruses	Publication Date: May 16, 2017
Citations: 23	License type: CC BY 4.0

Affiliation: University of Maryland, Baltimore, University of Padua

Abstract

Chemokine receptor type 6 (CCR6)+CD4+ T cells are preferentially infected and depleted during HIV disease progression, but are preserved in non-progressors. CCR6 is expressed on a heterogeneous population of memory CD4+ T cells that are critical to mucosal immunity. Preferential infection of these cells is associated, in part, with high surface expression of CCR5, CXCR4, and α4β7. In addition, CCR6+CD4+ T cells harbor elevated levels of integrated viral DNA and high levels of proliferation markers. We have previously shown that the CCR6 ligands MIP-3α and human beta defensins inhibit HIV replication. The inhibition required CCR6 and the induction of APOBEC3G. Here, we further characterize the induction of apolipoprotein B mRNA editing enzyme (APOBEC3G) by human beta defensin 2. Human beta defensin 2 rapidly induces transcriptional induction of APOBEC3G that involves extracellular signal-regulated kinases 1/2 (ERK1/2) activation and the transcription factors NFATc2, NFATc1, and IRF4. We demonstrate that human beta defensin 2 selectively protects primary CCR6+CD4+ T cells infected with HIV-1. The selective protection of CCR6+CD4+ T cell subsets may be critical in maintaining mucosal immune function and preventing disease progression.

Highlights

HIV preferentially infects and depletes chemokine receptor type 6 (CCR6)+ CD4+ T cells despite suppressive antiretroviral therapy [1,2]
CCR6+ CD4+ T cells are preferentially infected by HIV-1 and depleted [1,2]
HIV-1-infected long-term non-progressors and simian immunodeficiency virus (SIV)-infected sooty mangabeys, which do not progress to AIDS and lack both microbial translocation and chronic immune activation, maintain levels of Th17 cells in both the blood and gut [21,28,30]. These findings suggest that protecting CCR6+ CD4+ T cell subsets may be critical in preventing disease progression, and human beta defensin 2 (hBD2) produced from mucosal epithelial cells could contribute to preserving this subset (Figure 6)

Summary

Introduction

HIV preferentially infects and depletes chemokine receptor type 6 (CCR6)+ CD4+ T cells despite suppressive antiretroviral therapy [1,2]. CCR6 is a marker of memory CD4+ T cells that express the HIV co-receptors, CCR5 and CXC chemokine receptors type 4 (CXCR4), and the integrin α4β7 [2,10]. CCR6 is a marker of Th17 cells which express CXCR4 and often express CCR5 [11,12,13]. The high proportion and increased expression of CCR5 and α4β7 enhances entry and HIV envelope binding to CCR6+ CD4+ T cells [2,13,14]

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