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 Gorodezky, James V. Falvo, Judy Lieberman, Premlata Shankar, Anne E. Goldfeld

Research output: Contribution to journalArticle

26 Citations (Scopus)

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)
JournalPLoS Pathogens
Volume2
Issue number12
DOIs
StatePublished - Dec 2006
Externally publishedYes

Fingerprint

NFATC Transcription Factors
Terminal Repeat Sequences
HIV-1
Monocytes
Simian Immunodeficiency Virus
RNA Interference
Transcription Factors
Macrophages
Nucleotide Motifs
HIV-2
Deoxyribonuclease I
Mutagenesis
Small Interfering RNA
Transfection
Organism Cloning
Acquired Immunodeficiency Syndrome
Binding Sites
Viruses

ASJC Scopus subject areas

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

Cite this

NFAT5 regulates HIV-1 in primary monocytes via a highly conserved long terminal repeat site. / Ranjbar, Shahin; Tsytsykova, Alla V.; Lee, Sang Kyung; Rajsbaum Gorodezky, Ricardo; Falvo, James V.; Lieberman, Judy; Shankar, Premlata; Goldfeld, Anne E.

In: PLoS Pathogens, Vol. 2, No. 12, 12.2006.

Research output: Contribution to journalArticle

Ranjbar, S, Tsytsykova, AV, Lee, SK, Rajsbaum Gorodezky, R, Falvo, JV, Lieberman, J, Shankar, P & Goldfeld, AE 2006, 'NFAT5 regulates HIV-1 in primary monocytes via a highly conserved long terminal repeat site.', PLoS Pathogens, vol. 2, no. 12. https://doi.org/10.1371/journal.ppat.0020130
Ranjbar, Shahin ; Tsytsykova, Alla V. ; Lee, Sang Kyung ; Rajsbaum Gorodezky, Ricardo ; Falvo, James V. ; Lieberman, Judy ; Shankar, Premlata ; Goldfeld, Anne E. / NFAT5 regulates HIV-1 in primary monocytes via a highly conserved long terminal repeat site. In: PLoS Pathogens. 2006 ; Vol. 2, No. 12.
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