Comprehensive Analysis of HERV Transcriptome in HIV+ Cells: Absence of HML2 Activation and General Downregulation of Individual HERV Loci.

Enzo Tramontano,Maria Paola Pisano,Nicole Grandi,Sante Scognamiglio,Eleonora Pessiu

doi:10.3390/v12040481

Enzo Tramontano, Maria Paola Pisano + Show 3 more

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https://doi.org/10.3390/v12040481

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Abstract

Human endogenous retrovirus (HERV) expression is currently studied for its possible activation by HIV infection. In this context, the HERV-K(HML2) group is the most investigated: it has been proposed that HIV-1 infection can prompt HML2 transcription, and that HML2 proteins can affect HIV-1 replication, either complementing HIV or possibly influencing antiretroviral therapy. However, little information is available on the expression of other HERV groups in HIV infection. In the present study, we used a bioinformatics pipeline to investigate the transcriptional modulation of approximately 3250 well-characterized HERV loci, comparing their expression in a public RNA-seq profile, including a HIV-1-infected and a control T cell culture. In our pilot study, we found approximately 200 HERV loci belonging to 35 HERV groups that were expressed in one or both conditions, with transcripts per million (TPM) values from 1 to >500. Intriguingly, HML2 elements constituted only the 3% of expressed HERV loci, and in most cases (160) HERV expression was downregulated in the HIV-infected culture, showing from a 1- to 14-fold decrease as compared to uninfected cells. HERV transcriptome has been inferred de novo and employed to predict a total of about 950 HERV open reading frames (ORFs). These have been validated according to the coding potential and estimated abundance of the corresponding transcripts, leading to a set of 57 putative proteins potentially encoded by 23 HERV loci. Analysis showed that some individual loci have a coding potential that deserves further investigation. Among them, a HML6 provirus at locus 19q13.43 was predicted to produce a transcript showing the highest TPM among HERV-derived transcripts, being upregulated in HIV+ cells and inferred to produce Gag and Env puteins with possible biological activity.

Highlights

Human endogenous retroviruses (HERVs) are genomic remnants of past infections, sustained by ancestral exogenous retroviruses that became extinct millions of years ago
The expressed HERV loci showed higher transcripts per million (TPM) values in the uninfected cell culture, being mostly downregulated (146 out of 177) in the presence of HIV infection
Another study reported an absence of variation in HML2 RNA between infected and uninfected women, but observing an increase of HERV-W expression in HIV-infected mothers that was associated with a slight downregulation in HIV-exposed babies as compared to non-exposed ones [29]

Summary

Introduction

Human endogenous retroviruses (HERVs) are genomic remnants of past infections, sustained by ancestral exogenous retroviruses that became extinct millions of years ago. It has been hypothesized that HERV transcripts might trigger cellular antiviral defenses through the formation of double strand RNAs (dsRNA) between antisense homologous mRNA sequences, activating innate immunity effectors [4,5]. Another putative antiviral effect exerted by HERV proteins might be based on receptor interference and blocking, which confer partial resistance to exogenous infections, as observed with some animal ERVs [6,7]. Most of these interactions imply a certain degree of sequence and protein homology and are more prone to occur between endogenous and exogenous retroviruses

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