Transcriptome Analyses Implicate Endogenous Retroviruses Involved in the Host Antiviral Immune System through the Interferon Pathway

Miao Wang,Haizhou Liu,Liying Wang,Di Liu,Jianjun Chen

doi:10.1007/s12250-021-00370-2

Abstract

Human endogenous retroviruses (HERVs) are the remains of ancient retroviruses that invaded our ancestors’ germline cell and were integrated into the genome. The expression of HERVs has always been a cause for concern because of its association with various cancers and diseases. However, few previous studies have focused on specific activation of HERVs by viral infections. Our previous study has shown that dengue virus type 2 (DENV-2) infection induces the transcription of a large number of abnormal HERVs loci; therefore, the purpose of this study was to explore the relationship between exogenous viral infection and HERV activation further. In this study, we retrieved and reanalyzed published data on 21 transcriptomes of human cells infected with various viruses. We found that infection with different viruses could induce transcriptional activation of HERV loci. Through the comparative analysis of all viral datasets, we identified 43 key HERV loci that were up-regulated by DENV-2, influenza A virus, influenza B virus, Zika virus, measles virus, and West Nile virus infections. Furthermore, the neighboring genes of these HERVs were simultaneously up-regulated, and almost all such neighboring genes were interferon-stimulated genes (ISGs), which are enriched in the host’s antiviral immune response pathways. Our data supported the hypothesis that activation of HERVs, probably via an interferon-mediated mechanism, plays an important role in innate immunity against viral infections.

Highlights

Through the comparative analysis of all viral datasets, we identified 43 key Human endogenous retroviruses (HERVs) loci that were up-regulated by dengue virus type 2 (DENV-2), influenza A virus, influenza B virus, Zika virus, measles virus, and West Nile virus infections
To explore whether this phenomenon is ubiquitous in viral infections, we used data obtained by the infection of human cells with multiple exogenous viruses to study the activation of HERV
The hepatitis C virus (HCV), Crimean-Congo hemorrhagic fever virus (CCHFV), and RHV groups contained RNA-seq data obtained after different hours post infection; we found that exogenous viral infections affected the expressions of HERVs in a time-dependent manner

Summary

Introduction

Human endogenous retroviruses (HERVs) are derived from multiple independent integrations of exogenous retroviruses in our ancestor’s germ cell, most of which are more than 30 million years old (Bannert and Kurth 2006). Some HERV elements were amplified within the genome via re-infection or intracellular retrotransposition (Dewannieux and Heidmann 2013); HERVs currently account for about 8% of the human genome (for protein-coding genes, about 1%) (Lander et al 2001; Harrow et al 2009). Most HERVs in our genome contain no internal genes but solo-LTR (long-terminal repeat), which is a result of the recombination of 50 and 30 LTRs (Bolze et al 2017). The sequences of present-day HERVs are highly diverse and show defective replication. Traditional studies on HERVs have mostly focused on their relationship with cancer (Golan et al 2008; Kahyo et al 2013), pluripotency (Romer et al 2017), and neurological diseases (Kury et al 2018)

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