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.
Highlights
It is well known that noncoding RNAs are implicated in a wide variety of cellular processes through posttranscriptional regulation of protein expression
The initial reports of siRNA mediated activation related to three genes: E-cadherin, p21, and vascular endothelial growth factor (VEGF) and the effect was shown in prostate cancer cell lines, PC-3 and DU-145, and the human breast cancer cell line, MCF-7.105 The authors further investigated the mechanism of transcriptional activation of p21 in the PC-3 cell line and identified the antisense strand of siRNA and Ago[2] as being the critical components for this activation, which was associated with loss of methylation of lysine-9 of histone 3 in the chromatin adjacent to dsRNA-target sites
The outcome is dependent on the targeted promoter and probably on availability and the relative abundance of different species of ncRNAs, including long asRNAs, miRNAs, and antisense-siRNAs in latently infected cells
Summary
It is well known that noncoding RNAs (ncRNAs) are implicated in a wide variety of cellular processes through posttranscriptional regulation of protein expression. A different approach, aimed at activating the virus by altering the epigenetic profile of the latent virus, has employed Histone deacetylase (HDAC) inhibitors (HDACi), such as valproic acid (VPA), suberoylanilide hydroxamic acid (SAHA, vorinostat), romidepsin, and parabinostat.[38,39,40,41,42,43] these drugs have the ability to reactivate some integrated virus in vitro, so far, these agents have resulted in quite limited viral reactivation in vivo, while causing significant activation of a range of host genes.[13,44] This suboptimal response suggests that a more focused approach is required to increase the specificity of such interventions This is supported by the recently reported observation that vorinostat can inhibit cytotoxic T-lymphocyte (CTL) function.[45] This interaction has the potential to substantially limit the effectiveness of HDACi in the “Kick and Kill Approach,” as it was hoped that CTL would mediate the “killing” once latently infected cells were “kicked” into expressing viral antigens.[45]. Recent reports have suggested that ncRNAs including miRNA, siRNA, and asRNA, are associated with the regulation of the viral latency.[46,47] these molecules may provide the actual tools, or at least insights into mechanisms, that will allow specific regulation of viral latency
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