FoxP3 Enhances HIV-1 Gene Expression by Modulating NFκB Occupancy at the Long Terminal Repeat in Human T Cells*
- ‡Department of Microbiology and Immunology, the §Lineberger Comprehensive Cancer Center, and the ¶Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina 27599-7295
- 1 To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7295. Tel.: 919-966-6654; Fax: 919-966-8212; E-mail: lsu{at}med.unc.edu.
Abstract
FoxP3 determines the development of CD4+CD25+ regulatory T (Treg) cells and represses interleukin-2 (IL-2) expression in Treg cells. However, human immunodeficiency virus type 1 (HIV-1) infects and replicates efficiently in FoxP3+ Treg cells. We report that, while inhibiting IL-2 gene expression, FoxP3 enhances gene expression from HIV-1 long terminal repeat (LTR). This FoxP3 activity requires both the N- and C-terminal domains and is inactivated by human IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) mutations. FoxP3 enhances HIV-1 LTR via its specific NFκB binding sequences in an NFκB-dependent fashion in T cells but not in HEK293 cells. FoxP3 decreases level of histone acetylation at the interleukin-2 locus but not at the HIV-1 LTR. Although NFκB nuclear translocation is not altered, FoxP3 enhances NFκB-p65 binding to HIV-1 LTR. These data suggest that FoxP3 modulates gene expression in a promoter sequence-dependent fashion by modulating chromatin structure and NFκB activity. HIV-1 LTR has evolved to both highjack the T-cell activation pathway for expression and to resist FoxP3-mediated suppression of T-cell activation.
Footnotes
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↵2 The abbreviations used are: Treg, regulatory T cell; IPEX, immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; IL-2, interleukin-2; HIV-1, human immunodeficiency virus, type 1; SIV, simian immunodeficiency virus; LTR, long terminal region; MHC, major histocompatibility complex; aa, amino acid(s); NFAT, nuclear factor of activated T cells; GFP, green fluorescent protein; VSV-G, vesicular stomatitis virus glycoprotein; qPCR, quantitative PCR.
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↵3 D. Holmes and L. Su, unpublished results.
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↵* The project was supported by National Institutes of Health Grants AI048407 (to L. S.) and 5T32AI07273 (to G. K.). The authors declare no competing financial interests. 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.
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The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.
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- Received March 8, 2007.
- Revision received March 28, 2007.
