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Human Beta Defensin 2 Selectively Inhibits HIV-1 in Highly Permissive CCR6⁺CD4⁺ T Cells
Mark K Lafferty1,2, Lingling Sun3, Aaron Christensen-Quick4,5
1Division of Basic Science, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. mark.lafferty@umaryland.edu.
Insights
Human beta defensin 2 protects specific CD4+ T cells from HIV-1 infection by inducing APOBEC3G. This selective protection of CCR6+ CD4+ T cells may be key to maintaining mucosal immunity and slowing HIV disease progression.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Chemokine receptor type 6 (CCR6)+ CD4+ T cells are crucial for mucosal immunity and are preferentially infected and depleted during HIV progression.
- These cells express high levels of CCR5, CXCR4, and α4β7, and harbor elevated viral DNA and proliferation markers, making them vulnerable to HIV-1.
- Previous studies showed CCR6 ligands inhibit HIV replication via APOBEC3G induction.
Purpose of the Study:
- To further characterize the induction of apolipoprotein B mRNA editing enzyme (APOBEC3G) by human beta defensin 2 (HBD2).
- To investigate the protective effect of HBD2 on primary CCR6+ CD4+ T cells infected with HIV-1.
Main Methods:
- Investigated HBD2-induced transcriptional induction of APOBEC3G.
- Analyzed the involvement of extracellular signal-regulated kinases 1/2 (ERK1/2) and transcription factors NFATc2, NFATc1, and IRF4.
- Assessed the selective protection of primary CCR6+ CD4+ T cells against HIV-1 infection.
Main Results:
- HBD2 rapidly induces transcriptional upregulation of APOBEC3G.
- This induction involves ERK1/2 activation and the transcription factors NFATc2, NFATc1, and IRF4.
- HBD2 selectively protects primary CCR6+ CD4+ T cells from HIV-1 infection.
Conclusions:
- HBD2-mediated induction of APOBEC3G provides selective protection to CCR6+ CD4+ T cells against HIV-1.
- This selective protection mechanism may be vital for preserving mucosal immune function and mitigating HIV disease progression.
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.
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