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

Shahin Ranjbar, Alla V. Tsytsykova, Sang Kyung Lee, Ricardo Rajsbaum, James V. Falvo, Judy Lieberman, Premlata Shankar, Anne E. Goldfeld

Research output: Contribution to journalArticle

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1176-1186
Number of pages11
JournalPLoS pathogens
Volume2
Issue number12
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Ranjbar, S., Tsytsykova, A. V., Lee, S. K., Rajsbaum, R., Falvo, J. V., Lieberman, J., Shankar, P., & Goldfeld, A. E. (2006). NFAT5 regulates HIV-1 in primary monocytes via a highly conserved long terminal repeat site. PLoS pathogens, 2(12), 1176-1186. https://doi.org/10.1371/journal.ppat.0020130