NFAT5 regulates HIV-1 in primary monocytes via a highly conserved long terminal repeat site.

Abstract:

:To replicate, HIV-1 capitalizes on endogenous cellular activation pathways resulting in recruitment of key host transcription factors to its viral enhancer. RNA interference has been a powerful tool for blocking key checkpoints in HIV-1 entry into cells. Here we apply RNA interference to HIV-1 transcription in primary macrophages, a major reservoir of the virus, and specifically target the transcription factor NFAT5 (nuclear factor of activated T cells 5), which is the most evolutionarily divergent NFAT protein. By molecularly cloning and sequencing isolates from multiple viral subtypes, and performing DNase I footprinting, electrophoretic mobility shift, and promoter mutagenesis transfection assays, we demonstrate that NFAT5 functionally interacts with a specific enhancer binding site conserved in HIV-1, HIV-2, and multiple simian immunodeficiency viruses. Using small interfering RNA to ablate expression of endogenous NFAT5 protein, we show that the replication of three major HIV-1 viral subtypes (B, C, and E) is dependent upon NFAT5 in human primary differentiated macrophages. Our results define a novel host factor-viral enhancer interaction that reveals a new regulatory role for NFAT5 and defines a functional DNA motif conserved across HIV-1 subtypes and representative simian immunodeficiency viruses. Inhibition of the NFAT5-LTR interaction may thus present a novel therapeutic target to suppress HIV-1 replication and progression of AIDS.

journal_name

PLoS Pathog

journal_title

PLoS pathogens

authors

Ranjbar S,Tsytsykova AV,Lee SK,Rajsbaum R,Falvo JV,Lieberman J,Shankar P,Goldfeld AE

doi

10.1371/journal.ppat.0020130

subject

Has Abstract

pub_date

2006-12-01 00:00:00

pages

e130

issue

12

eissn

1553-7366

issn

1553-7374

pii

06-PLPA-RA-0290R3

journal_volume

2

pub_type

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