regulation of mycobacterium tuberculosis-dependent hiv-1 transcription reveals a new role for nfat5 in the toll-like receptor pathway调节分枝杆菌tuberculosis-dependent hiv - 1转录揭示了一个新的角色的nfat5 toll样受体途径.pdfVIP

Regulation of Mycobacterium tuberculosis-Dependent HIV-1 Transcription Reveals a New Role for NFAT5 in the Toll-Like Receptor Pathway 1,2 1 1 1,3 Shahin Ranjbar , Luke D. Jasenosky , Nancy Chow , Anne E. Goldfeld * 1 Immune Disease Institute and Program in Cellular and Molecular Medicine, Children’s Hospital Boston, Boston, Massachusetts, United States of America, 2 Department of Pediatrics Harvard Medical School, Boston, Massachusetts, United States of America, 3 Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America Abstract Tuberculosis (TB) disease in HIV co-infected patients contributes to increased mortality by activating innate and adaptive immune signaling cascades that stimulate HIV-1 replication, leading to an increase in viral load. Here, we demonstrate that silencing of the expression of the transcription factor nuclear factor of activated T cells 5 (NFAT5) by RNA interference (RNAi) inhibits Mycobacterium tuberculosis (MTb)-stimulated HIV-1 replication in co-infected macrophages. We show that NFAT5 gene and protein expression are strongly induced by MTb, which is a Toll-like receptor (TLR) ligand, and that an intact NFAT5 binding site in the viral promoter of R5-tropic HIV-1 subtype B and subtype C molecular clones is required for efficent induction of HIV-1 replication by MTb. Furthermore, silencing by RNAi of key components of the TLR pathway in human monocytes, including the downstream signaling molecules MyD88, IRAK1, and TRAF6, significantly inhibits MTb- induced NFAT5 gene expression. Thus, the innate immune response to MTb infection induces NFAT5 gene and protein expression, and NFAT5 plays a crucial role in MTb regulation of HIV-1 replication via a direct i