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Review
. 2015 Jan 27;4(1):e222.
doi: 10.1038/mtna.2014.67.

Promoter Targeting RNAs: Unexpected Contributors to the Control of HIV-1 Transcription

Kazuo Suzuki  1 , Chantelle Ahlenstiel  2 , Katherine Marks  3 , Anthony D Kelleher  1
Affiliations
Review

Promoter Targeting RNAs: Unexpected Contributors to the Control of HIV-1 Transcription

Kazuo Suzuki et al. Mol Ther Nucleic Acids. .

Abstract

In spite of prolonged and intensive treatment with combined antiretroviral therapy (cART), which efficiently suppresses plasma viremia, the integrated provirus of HIV-1 persists in resting memory CD4(+) T cells as latent infection. Treatment with cART does not substantially reduce the burden of latent infection. Once cART is ceased, HIV-1 replication recrudesces from these reservoirs in the overwhelming majority of patients. There is increasing evidence supporting a role for noncoding RNAs (ncRNA), including microRNAs (miRNAs), antisense (as)RNAs, and short interfering (si)RNA in the regulation of HIV-1 transcription. This appears to be mediated by interaction with the HIV-1 promoter region. Viral miRNAs have the potential to act as positive or negative regulators of HIV transcription. Moreover, inhibition of virally encoded long-asRNA can induce positive transcriptional regulation, while antisense strands of siRNA targeting the NF-κB region suppress viral transcription. An in-depth understanding of the interaction between ncRNAs and the HIV-1 U3 promoter region may lead to new approaches for the control of HIV reservoirs. This review focuses on promoter associated ncRNAs, with particular emphasis on their role in determining whether HIV-1 establishes active or latent infection.

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Figures

Figure 1
Figure 1
Schematic of noncoding RNAs interacting with the HIV-1 promoter region. After HIV-1 is integrated into the human genome, nucleosomes are precisely embedded within the U3 promoter region of 5′ LTR. Nuc-0 is located at the start of the U3 promoter region and Nuc-1 is located at the start of the “R” region. Transcription is initiated in the R region, indicated by the arrow., Various host transcriptional regulators interact with the U3 promoter region; predicted binding sites for transcription activators such as Nuclear Factor-κB (NF-κB), Nuclear Factor of Activated T-cell protein (NFAT), Specificity Protein 1 (SP1), TATA-box, T-cell–specific factor-1α (TCF-1α), and Activator Protein 1 (AP-1) are shown. The binding site of transcription repressor, Yin Yang 1 (YY1), is also shown. Various species of promoter associated ncRNAs including, long antisense RNAs (long asRNA)/antisense long noncoding RNAs (antisense lncRNAs) (light orange), miRNAs (red), and siRNAs (blue) are shown above the U3 promoter region (see text for detail).
Figure 2
Figure 2
Graphic representation of the in vivo effects of a promoter targeted siRNA approach in a humanized mouse model. (a–b) Replication-incompetent lentivirus, (b) shPromA-JRFL or (a) control lentivirus shPromA-M2, is transfected into CD4+ T cells obtained from healthy control PBMCs. Transduced PBMCs are transplanted into (NOD)/SCID/Janus kinase 3 (NOJ) knockout mice, transplantation occurs. The humanized mice are then challenged with HIV-1 and sacrificed 14 days postchallenge. The antisense strand of shPromA-JRFL (shown in red), in association with Ago1 (purple) and other RITS-like complex components (HDAC-yellow, EZH2-pink), induces heterochromatin formation and methylation marks (H3K9me2, indicated by stars) in the targeted HIV-1 promoter region to suppress HIV-1 transcription and results in protection of CD4+ T cells, resulting in lower pVL than mice transplanted with shPromA-M2 control lentivirus transduced PBMCs.
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