lncRNA discovery in the HIV replication cycle adds new layer in HIV-host interplay

Studying the effects of HIV infection on the host transcriptome has typically focused on protein-coding genes. However, recent advances in the field of RNA sequencing revealed that long non-coding RNAs (lncRNAs) add an extensive additional layer to the cell's molecular network and are crucial for normal cellular function. lncRNAs exert the ability to control a wide range of (post-)transcriptional processes and offer unique possibilities for pathogens like HIV to hijack the cellular machinery and reshape gene expression in their favor. Therefore, lncRNA discovery can result in new insights into the HIV-host interplay. We performed transcriptome profiling throughout a characterized primary HIV infection in vitro to investigate lncRNA expression at the different HIV replication cycle processes (reverse transcription, integration and particle production). Subsequently, guilt-by-association, transcription factor and co-expression analysis were performed to infer biological roles for the lncRNAs identified in the HIV-host interplay. Throughout the HIV replication cycle we identified 387 lncRNAs that were differentially expressed with the majority observed at the viral integration phase. Many of these lncRNAs (173) were suggested to play a role in mechanisms at the heart of HIV-host interplay that rely on proteasomal and ubiquitination pathways (113), apoptosis inhibition (12), BRCA1/2 DNA damage responses and ATR cell cycle regulation (12). Through transcription factor binding analysis, we found that lncRNAs display a distinct transcriptional regulation profile (ao. TAF1/3/7, CHD1 and AT3) as compared to protein coding mRNAs (ao. KLF4, SUZ12 and SOX2), suggesting that mRNAs and lncRNAs are independently modulated during HIV replication. In addition, we identified five differentially expressed lncRNA-mRNA pairs with mRNA involvement in HIV pathogenesis with possible cis regulatory lncRNAs that control nearby mRNA expression and function (ao. lnc-HES5-1 and TNFRSF14). Altogether, the present study demonstrates that lncRNAs add a new dimension to the HIV-host interplay and exhibit an independent transcriptionally regulated response. These identified lncRNAs are involved in viral and antiviral response pathways and should be further investigated as they may represent possible biomarkers or targets for controlling HIV replication.

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