Premium
Sterol regulatory element‐binding protein 2 (SREBP‐2) couples cholesterol homeostasis and T cell activation to HIV‐1 transcription
Author(s) -
Taylor Harry Eugene,
Hildreth James E. K.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.537.2
Subject(s) - sterol regulatory element binding protein , transcription factor , gene silencing , gene knockdown , transcription (linguistics) , microbiology and biotechnology , biology , response element , cell culture , gene expression , gene , biochemistry , promoter , genetics , linguistics , philosophy
HIV‐1 replication in primary human CD4 + T cells requires cellular activation and host cholesterol for productive infection. Interestingly, both T cell activation and HIV‐1 infection independently induce SREBP‐2‐dependent transcription. Oxysterols that suppress host cell cholesterol‐dependent transcription by inhibiting SREBP‐2 processing also inhibit HIV‐1 replication in vitro . Using bioinformatic and molecular approaches, we have identified TFII‐I, a transcription factor critical for T cell receptor‐mediated HIV‐1 LTR transcription, as a novel SREBP‐2 target gene in CD4 + T cells. Levels of TFII‐I in CD4 + T cells increased after HIV‐1 infection and correlated with the level of T cell activation. Reduction of endogenous SREBP‐2 activity by 25‐hydroxycholesterol treatment or siRNA‐mediated silencing inhibited induction of TFII‐I in both activated and HIV‐1 infected primary CD4 + T cells. Correspondingly, depletion of SREBP‐2 reduced HIV‐1 replication in CD4 + T cells by more than 75%. Consistent with a role in HIV‐1 LTR transcription, siRNA‐mediated knockdown of either SREBP‐2 or TFII‐I reduced intracellular viral antigen levels in HIV‐1‐infected CD4 + T cells. Collectively, these results demonstrate that control of TFII‐I expression via SREBP‐2 is essential for HIV‐1 replication. Inhibition of this pathway may provide a new therapeutic strategy for AIDS. Supported by NIH (R01 HD040772 )