Differential expression of lncRNAs during the HIV replication cycle: an underestimated layer in the HIV-host interplay.

Wim Trypsteen,Steve Lefever,Ward De Spiegelaere,Pejman Mohammadi,Yvan Saeys,Clarissa Van Hecke,Pieter Mestdagh,Jo Vandesompele,Linos Vandekerckhove,Pieter De Bleser,Angela Ciuffi

doi:10.1038/srep36111

Abstract

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. Here, we performed transcriptome profiling throughout a 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. Many lncRNAs were suggested to play a role in mechanisms relying on proteasomal and ubiquitination pathways, apoptosis, DNA damage responses and cell cycle regulation. Through transcription factor binding analysis, we found that lncRNAs display a distinct transcriptional regulation profile as compared to protein coding mRNAs, suggesting that mRNAs and lncRNAs are independently modulated. 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. Altogether, the present study demonstrates that lncRNAs add a new dimension to the HIV-host interplay and should be further investigated as they may represent targets for controlling HIV replication.

Highlights

The interplay between the human immunodeficiency virus (HIV) and the host’s cellular defenses has been broadly studied to elucidate the underlying viral and antiviral molecular mechanisms
LncRNA expression might be influenced to a larger extent than mRNAs because the datasets differ in the time points considered for transcriptome profiling
The present study provides a comprehensive map of differentially expressed long (>200 nt) non-coding RNAs (lncRNAs) throughout the HIV replication cycle and reveals a new and underestimated dimension in the HIV-host interplay

Summary

Introduction

The interplay between the human immunodeficiency virus (HIV) and the host’s cellular defenses has been broadly studied to elucidate the underlying viral and antiviral molecular mechanisms. These studies typically focused on protein-coding genes and successfully identified several host factors involved in HIV pathogenesis and intracellular defense[1,2,3,4,5,6]. Over the past decade it has become evident from genome-wide tiling arrays and RNA sequencing studies that the human genome is pervasively transcribed and that the majority of these transcribed genomic sequences are associated with non-coding RNAs (ncRNAs) rather than protein coding RNAs, underpinning their widespread presence in the cellular environment and adding a new layer of complexity to the cell’s molecular network[7,8,9,10]. We present a focused extension study of a unique HIV time course experiment and investigate lncRNA expression in the context of an HIV infection to shed light on the HIV-lncRNA regulatory landscape[23]

Methods

Results

Discussion

Conclusion