FoxP3 enhances HIV-1 gene expression by modulating NFkappaB occupancy at the long terminal repeat in human T cells.
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 NFkappaB binding sequences in an NFkappaB-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 NFkappaB nuclear translocation is not altered, FoxP3 enhances NFkappaB-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 NFkappaB 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.
Holmes
Derek
D
Department of Microbiology and Immunology, the Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill 27599-7295, USA.
Knudsen
Geoffry
G
Mackey-Cushman
Stephanie
S
Su
Lishan
L
D000107:Acetylation; D021581:Active Transport, Cell Nucleus / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D002843:Chromatin / Q000378:metabolism / Q000821:virology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D009154:Mutation; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism* / Q000821:virology; D051996:Transcription Factor RelA / Q000378:metabolism*; D014779:Virus Replication / Q000235:genetics
D002843:Chromatin; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006657:Histones; C508594:IL2 protein, human; D007376:Interleukin-2; D051996:Transcription Factor RelA