Functional interactions between C/EBP, Sp1, and COUP-TF regulate human immunodeficiency virus type 1 gene transcription in human brain cells.

in Journal of virology by C Schwartz, P Catez, O Rohr, D Lecestre, D Aunis, E Schaeffer

TLDR

  • This study looked at how a virus called HIV-1 infects the brain and how it's controlled in the brain. The study found that a protein called NF-IL6 helps control how the virus is made in the brain. The study also found that another protein called C/EBPgamma helps control how NF-IL6 works. The study also looked at how other proteins called Sp1 and COUP-TF work with NF-IL6 and C/EBPgamma to control how the virus is made in the brain.

Abstract

Human immunodeficiency virus type 1 (HIV-1) infects the central nervous system (CNS) and plays a direct role in the pathogenesis of AIDS dementia. However, mechanisms underlying HIV-1 gene expression in the CNS are poorly understood. The importance of CCAAT/enhancer binding proteins (C/EBP) for HIV-1 expression in cells of the immune system has been recently reported. In this study, we have examined the role and the molecular mechanisms by which proteins of the C/EBP family regulate HIV-1 gene transcription in human brain cells. We found that NF-IL6 acts as a potent activator of the long terminal repeat (LTR)-driven transcription in microglial and oligodendroglioma cells. In contrast, C/EBPgamma inhibits NF-IL6-induced activation. Consistent with previous data, our transient expression results show cell-type-specific NF-IL6-mediated transactivation. In glial cells, full activation needs the presence of the C/EBP binding sites; however, NF-IL6 is still able to function via the minimal -40/+80 region. In microglial cells, C/EBP sites are not essential, since NF-IL6 acts through the -68/+80 LTR region, containing two binding sites for the transcription factor Sp1. Moreover, we show that functional interactions between NF-IL6 and Sp1 lead to synergistic transcriptional activation of the LTR in oligodendroglioma and to mutual repression in microglial cells. We further demonstrate that NF-IL6 physically interacts with the nuclear receptor chicken ovalbumin upstream promoter transcription factor (COUP-TF), via its DNA binding domain, in vitro and in cells, which results in mutual transcriptional repression. These findings reveal how the interplay of NF-IL6 and C/EBPgamma, together with Sp1 and COUP-TF, regulates HIV-1 gene transcription in brain cells.

Overview

  • The study examines the role and molecular mechanisms of C/EBP family proteins in regulating HIV-1 gene transcription in human brain cells. The study focuses on the importance of NF-IL6 and C/EBPgamma in this process and their interactions with other transcription factors such as Sp1 and COUP-TF. The primary objective of the study is to understand the mechanisms underlying HIV-1 gene expression in the CNS and identify potential targets for therapeutic interventions.

Comparative Analysis & Findings

  • The study found that NF-IL6 acts as a potent activator of LTR-driven transcription in microglial and oligodendroglioma cells, while C/EBPgamma inhibits NF-IL6-induced activation. The study also demonstrated that functional interactions between NF-IL6 and Sp1 lead to synergistic transcriptional activation of the LTR in oligodendroglioma and to mutual repression in microglial cells. Additionally, the study showed that NF-IL6 physically interacts with the nuclear receptor chicken ovalbumin upstream promoter transcription factor (COUP-TF), via its DNA binding domain, in vitro and in cells, which results in mutual transcriptional repression.

Implications and Future Directions

  • The study's findings provide insights into the molecular mechanisms underlying HIV-1 gene expression in the CNS and identify potential targets for therapeutic interventions. The study suggests that targeting NF-IL6 and C/EBPgamma could be an effective strategy for treating HIV-1-associated dementia. Future research could further explore the role of other transcription factors and their interactions in regulating HIV-1 gene transcription in the CNS, as well as investigate the potential of small molecule inhibitors to modulate these interactions.
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