Activation of the innate immune response by endogenous retroviruses

Hurst, Tara; Magiorkinis, Gkikas

doi:10.1099/jgv.0.000017

Cited by 108 publications

(96 citation statements)

References 95 publications

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“…In summary, the methylation levels of LTRs are different among ERV-DC loci, and these patterns are correlated with their genotypes. One of the major functions of DNA methylation is thought to be the silencing of ERVs (67)(68)(69), and ERV demethylation and expression cause an immune response (69,70). A similar phenomenon may occur in the association with ERV-DC gene regulation.…”

Section: Discussionmentioning

confidence: 97%

Existence of Two Distinct Infectious Endogenous Retroviruses in Domestic Cats and Their Different Strategies for Adaptation to Transcriptional Regulation

Kuse

Ito

Miyake

et al. 2016

J Virol

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Endogenous retroviruses (ERVs) are the remnants of ancient retroviral infections of germ cells. Previous work identified one of the youngest feline ERV groups, ERV-DC, and reported that two ERV-DC loci, ERV-DC10 and ERV-DC18 (ERV-DC10/DC18), can replicate in cultured cells. Here, we identified another replication-competent provirus, ERV-DC14, on chromosome C1q32. ERV-DC14 differs from ERV-DC10/DC18 in its phylogeny, receptor usage, and, most notably, transcriptional activities; although ERV-DC14 can replicate in cultured cells, it cannot establish a persistent infection owing to its low transcriptional activity. Furthermore, we examined ERV-DC transcription and its regulation in feline tissues. Quantitative reverse transcription-PCR (RT-PCR) detected extremely low ERV-DC10 expression levels in feline tissues, and bisulfite sequencing showed that 5= long terminal repeats (LTRs) of ERV-DC10/DC18 are significantly hypermethylated in feline blood cells. Reporter assays found that the 5=-LTR promoter activities of ERV-DC10/DC18 are high, whereas that of ERV-DC14 is low. This difference in promoter activity is due to a single substitution from A to T in the LTR, and reverse mutation at this nucleotide in ERV-DC14 enhanced its replication and enabled it to persistently infect cultured cells. Therefore, ERV-DC LTRs can be divided into two types based on this nucleotide, the A type or T type, which have strong or attenuated promoter activity, respectively. Notably, ERV-DCs with T-type LTRs, such as ERV-DC14, have expanded in the cat genome significantly more than A-type ERV-DCs, despite their low promoter activities. Our results provide insights into how the host controls potentially infectious ERVs and, conversely, how ERVs adapt to and invade the host genome. IMPORTANCEThe domestic cat genome contains many endogenous retroviruses, including ERV-DCs. These ERV-DCs have been acquired through germ cell infections with exogenous retroviruses. Some of these ERV-DCs are still capable of producing infectious virions. Hosts must tightly control these ERVs because replication-competent viruses in the genome pose a risk to the host. Here, we investigated how ERV-DCs are adapted by their hosts. Replication-competent viruses with strong promoter activity, such as ERV-DC10 and ERV-DC18, were suppressed by promoter methylation in LTRs. On the other hand, replication-competent viruses with weak promoter activity, such as ERV-DC14, seemed to escape strict control via promoter methylation by the host. Interestingly, ERV-DCs with weak promoter activity, such as ERV-DC14, have expanded in the cat genome significantly more than ERV-DCs with strong promoter activity. Our results improve the understanding of the host-virus conflict and how ERVs adapt in their hosts over time. Endogenous retroviruses (ERVs) are resident DNA copies that abound in host chromosomal DNA and compromise ϳ8 to 10% of human and mouse genomes (1, 2). They have been found in all vertebrates, including mammals, fish, birds, reptiles, and amphibians (3). ERVs we...

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Section: Discussionmentioning

confidence: 97%

Existence of Two Distinct Infectious Endogenous Retroviruses in Domestic Cats and Their Different Strategies for Adaptation to Transcriptional Regulation

Kuse

Ito

Miyake

et al. 2016

J Virol

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“…The above data suggests Aza might activate endogenous retroviral sequences (ERVs) that constitute more than 8% of the human genome, can activate cytosolic RNA sensors, and are silenced in normal somatic cells by promoter DNA methylation (Bannert and Kurth, 2004) (Tristem, 2000) (Hurst and Magiorkinis, 2014) (Mankan et al, 2014). Some cancers lose ERV DNA methylation and aberrantly overexpress ERVs Cohen et al, 1988;Larsen et al, 2009;Larsson et al, 2007;Rycaj et al, 2014;Strick et al, 2007;Strissel et al, 2012;Wang-Johanning et al, 2001;Wang-Johanning et al, 2007) while others maintain silencing.…”

Section: Aza-induced Human Endogenous Retrovirus (Erv) Transcripts Camentioning

confidence: 99%

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Chiappinelli¹,

Strissel²,

Desrichard³

et al. 2017

Cell

105

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SummaryWe show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a Type I Interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response twofold, and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Correspondence should be addressed to Reiner.Strick@uk-erlangen.de and sbaylin@jhmi.edu.. 7 Co-first authors. 8 Co-senior authors.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Author Contributions KBC, PLS, AD, TM, JW, TAC, SBB, and RS designed experiments, performed data analyses, and wrote the manuscript. KBC, PLS, CH, AD, AH, BA, and SB performed experiments. NSR provided ERV-3 env cDNA plasmid and DS provided ovarian cancer cell lines. HL, AS, VM, DMP, LMC, MWB, and CAZ assisted with data analyses. TM, TAC, SBB, and RS contributed equally to this work and are co-senior authors. HHS Public Access

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“…HERV Env proteins could also impair the immune response to exogenous pathogens and tumors. HERVs could have pathogenic potential through interaction with the immune response (Hurst and Magiorkinis, 2015).…”

Section: The Up-regulation Of Herv-k Is Induced By Exogenous Viruses mentioning

confidence: 99%

The involvement of human endogenous retroviruses K (HERV-K) in aging processes via induction of inflammation

Ochirov¹

2019

Preprint

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This detailed analysis provides an insight into aging processes in the human organism. The developmental program that controls the regulation of gene expression through epigenetic modifications leads to cellular senescence in the latter life. This epigenetic development system uses endogenous retroviruses and other retrotransposons as control elements that regulate gene expression through non-coding RNAs. Interaction with sex hormones causes activation of human endogenous retroviruses K (HERV-K) inducing a prolonged innate immune response and therefore chronic inflammation leading to complex changes in the signaling pathways inside the cell and thus contributes to age-associated phenotype in the form of tissue deterioration and may cause a spontaneous transition of tissues to cancer state.

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Activation of the innate immune response by endogenous retroviruses

Cited by 108 publications

References 95 publications

Existence of Two Distinct Infectious Endogenous Retroviruses in Domestic Cats and Their Different Strategies for Adaptation to Transcriptional Regulation

Existence of Two Distinct Infectious Endogenous Retroviruses in Domestic Cats and Their Different Strategies for Adaptation to Transcriptional Regulation

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

The involvement of human endogenous retroviruses K (HERV-K) in aging processes via induction of inflammation

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