Regulation of mycobacterium tuberculosis-dependent HIV-1 transcription reveals a new role for NFAT5 in the toll-like receptor pathway

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 interaction with the viral promoter. these findings also demonstrate a general role for nfat5 in tlr- and mtb-mediated control of gene expression. © 2012 ranjbar et al.