RNAi siRNA-induced DNA methylation of HIV-1 LTR

mpho.mosia

The aim here is to investigate non-integrated HIV-1 genomes by siRNA-induced promoter methylation, specifically in the 5’ Long-terminal repeat region

Investigating the central role of integration in HIV-1 –Mpho Mosia

Human immunodeficiency virus (HIV) is a global pandemic that requires alternative

therapeutic strategies, especially due to its latency which presents a major hurdle to

virus eradication in infected individuals. Although the current standard of treatment,

HAART seems to have had a significant improvement in prognosis, challenges related

to high costs, toxicity, patient compliance, and resistance associated with the life-long

treatment regimen, remain to be obstacles for adequate disease maintenance.

Previous studies have almost invariably focussed on exploring integration if HIV-1 viral

genomes, as an essential step of the retrovirus life-cycle. However, this integrated viral

DNA represents only a minor part of reverse-transcribed genomes.

What was once considered to be “dead-end” episomal DNA that renders nonintegrated

HIV-1 forms replication-defective, is now being deemed to be a myth. Nonintegrated

HIV-1 genomes have recently been reported to play a role in contributing

to viral propagation, persistence and treatment escape, thus demonstrating their

capability to aid in the regulation of HIV-1 latency.

This notion is supported by a number of studies revealing the help of integrated proviral

DNA in packaging episomally transcribed viral genomes into infectious particles, which

may contribute to their capability of expressing important HIV-1 regulatory proteins

such as those encoded by nef and tat.

Interestingly, the countenance of episomal HIV-1 is associated with epigenetic

silencing. In vitro studies have demonstrated increased expression of non-integrated

HIV-1 from exposure to histone deacetylase inhibitors (HDACi), a feature associated

transcriptionally silenced chromatin.

Furthermore, demethylating agents within the 5’ Long-terminal repeat (LTR) region of

HIV-1 provirus in chronically infected cell lines leads to the notion that perhaps

epigenetic is a preceding silencing is a mechanism which leads to subsequent nonintegrated

HIV-1 transcription and the expression of nef and tat proteins.

In this current era of gene-based therapeutics, RNA interference (RNAi) is increasingly

becoming a renowned field in the quest for conquering infectious disease. Small

interfering RNA (siRNA), one of the major contributing research tools in this field,

shows promise as an antiviral mechanism, which could better our understanding in

transcriptional processes for identifying drug targets to better manage HIV-1 latency.

Recently, studies reveal HIV-1 specific siRNAs to possess potent antiviral effects in a

variety of cell culture systems containing cognate sequences existing within different

regions of the HIV-1 genome. This subsequently culminates to inhibition of HIV

infection by specifically degrading genomic HIV-1 RNA in a number of systems

including permanent cell lines, primary CD4 positive T cells and macrophages.

Moreover, promoter methylation, shown to prolong the suppressive effect of siRNA on

productive HIV-1 infection, has been reported to result in transient suppression of the

virus through the degradation of viral transcripts. In this regard, CpG methylation of

important episomal genes of non-integrated HIV-1 DNA expressing nef and tat


proteins seems to be a promising knock-down approach that could lead to the

eradicating HIV-1 latency.

In this respect, I aim to investigate non-integrated HIV-1 genomes by siRNA-induced

promoter methylation, specifically in the 5’ LTR of this burdensome retroviral disease.

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