‘There and back again’: revisiting the pathophysiological roles of human endogenous retroviruses in the post-genomic era

Magiorkinis, Gkikas; Belshaw, Robert; Katzourakis, Aris

doi:10.1098/rstb.2012.0504

Cited by 64 publications

(74 citation statements)

References 154 publications

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“…One can define novel elements and seek to define the origins of ERVs (49). Transmissions between species and, more rarely, between different evolutionary orders can be demonstrated (24) and hypotheses regarding their possible pathogenic potential developed (50). One interesting set of data reveals that ERVs lacking an env gene have been particularly successful in amplifying their copy number (23), thus constituting genomic superspreaders.…”

Section: Structure and Classificationmentioning

confidence: 99%

Mammalian Endogenous Retroviruses

Mager

Stoye²

2015

Microbiol Spectr

167

103

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Over 40% of mammalian genomes comprise the products of reverse transcription. Among such retrotransposed sequences are those characterized by the presence of long terminal repeats (LTRs), including the endogenous retroviruses (ERVs), which are inherited genetic elements closely resembling the proviruses formed following exogenous retrovirus infection. Sequences derived from ERVs make up at least 8 to 10% of the human and mouse genomes and range from ancient sequences that predate mammalian divergence to elements that are currently still active. In this chapter we describe the discovery, classification and origins of ERVs in mammals and consider cellular mechanisms that have evolved to control their expression. We also discuss the negative effects of ERVs as agents of genetic disease and cancer and review examples of ERV protein domestication to serve host functions, as in placental development. Finally, we address growing evidence that the gene regulatory potential of ERV LTRs has been exploited multiple times during evolution to regulate genes and gene networks. Thus, although recently endogenized retroviral elements are often pathogenic, those that survive the forces of negative selection become neutral components of the host genome or can be harnessed to serve beneficial roles.

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Section: Structure and Classificationmentioning

confidence: 99%

Mammalian Endogenous Retroviruses

Mager

Stoye²

2015

Microbiol Spectr

167

103

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“…The combined direct and indirect effect of HDAC inhibitors could, in theory, lead to an overdrive of HERV activity with potential health risks (e.g. due to genomic instability [7,24]. We therefore measured the combined direct and indirect effect of HDAC inhibitors on HERV expression in J-LAT8.4 and U1 cells, which are models of HIV-1 latency in cell types that are subject to HIV-1 infection in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…Expression is most likely to be relevant and important for intact HERV genes, which would then result in potential health risks as a result of protein activity or an active retroviral replication cycle [24]. HERV-K (HML-2) (HK2) is the most recently active family [26] with intact open reading frames and transcription enhancers within intact long terminal repeats (LTRs).…”

Section: Introductionmentioning

confidence: 99%

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

et al. 2016

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Background: While antiretroviral therapies have improved life expectancy and reduced viral loads in HIV-1-positive individuals, the cessation of treatment results in a rebound of viral replication. This suggests that a reservoir of latently-infected cells remains within these patients, the identity of which is ill-defined and therefore difficult to target therapeutically. Current strategies are aimed at using drugs such as histone deacetylase (HDAC) inhibitors to induce the expression of latent HIV-1 proviruses in order to activate and ultimately eradicate this reservoir of infected cells. One concern with the use of HDAC inhibitors is that they could up-regulate human endogenous retroviruses (HERVs), as well as HIV-1, with potentially pathophysiological consequences. Results:In this study, we analysed the transcription of HERV genes in HIV-1 latency T cell (J-LAT 8.4) and monocyte (U1) models following treatment with the HDAC inhibitors, vorinostat, panobinostat and romidepsin. We examined the expression of HERV-K (HML-2) env and pol, as well as the co-opted genes HERV-W env (syncytin-1), HERV-FRD env (syncytin-2), in these cell lines. Finally, we investigated HERV expression in primary human T cells. Conclusions:We show that HDAC inhibitors did not substantially increase the transcription of the analysed HERV env or pol genes, suggesting that histone acetylation is not crucial for controlling HERV expression in these experimental models and in ex vivo primary human T cells. Importantly, this indicates that unwanted HERV expression does not appear to be a barrier to the use of HDAC inhibitors in HIV-1 cure strategies.

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“…Recombination or trans-complementation between these proviruses could lead to the formation of viruses that would be able to package and transmit HK2 sequences (9,(46)(47)(48), as seen with endogenous retroviruses in mice (49)(50)(51).…”

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confidence: 99%

Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences

Contreras-Galindo

Kaplan

Dube

et al. 2015

J Virol

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Human endogenous retroviruses (HERV) make up 8% of the human genome. While the youngest of these retroviruses, HERV-K(HML-2), termed HK2, is able to code for all viral proteins and produce virus-like particles, it is not known if these virus particles package and transmit HK2-related sequences. Here, we analyzed the capacity of HK2 for packaging and transmitting HK2 sequences. We created an HK2 probe, termed Bogota, which can be packaged into HK2 viruses, and transfected it into cells that make HK2 particles. Supernatants of the transfected cells, which contained HK2 viral particles, then were added to target cells, and the transmissibility of the HK2 Bogota reporter was tracked by G418 resistance. Our studies revealed that contemporary HK2 virions produced by some teratocarcinoma and breast cancer cell lines, as well as by peripheral blood lymphocytes from lymphoma patients, can package HK2 Bogota probes, and these viruses transmitted these probes to other cells. After transmission, HK2 Bogota transcripts undergo reverse transcription, a step impaired by antiretroviral agents or by introduction of mutations into the probe sequences required for reverse transcription. HK2 viruses were more efficiently transmitted in the presence of HK2 Rec or HIV-1 Tat and Vif. Transmitted Bogota probes formed episomes but did not integrate into the cellular genome. Resistance to integration might explain the relatively low number of HK2 insertions that were acquired during the last 25 million years of evolution. Whether transient transmission of modern HK2 sequences, which encode two putative oncoproteins, can lead to disease remains to be studied. IMPORTANCERetroviruses invaded the genome of human ancestors over the course of millions of years, yet these viruses generally have been inactivated during evolution, with only remnants of these infectious sequences remaining in the human genome. One of these viruses, termed HK2, still is capable of producing virus particles, although these particles have been regarded as being noninfectious. Using a genetic probe derived from HK2, we have discovered that HK2 viruses produced in modern humans can package HK2 sequences and transmit them to various other cells. Furthermore, the genetic sequences packaged in HK2 undergo reverse transcription. The transmitted probe circularized in the cell and failed to integrate into the cellular genome. These findings suggest that modern HK2 viruses can package viral RNA and transmit it to other cells. Contrary to previous views, we provide evidence of an extracellular viral phase of modern HK2 viruses. We have no evidence of sustained, spreading infection.A ctively replicating retroviruses infected the germ line multiple times over the millions of years of human evolution. These sequences were transmitted vertically in a Mendelian fashion to the next generation; therefore, they became a stable part of the inherited genetic material. Relics of these retroviral infections presently make up approximately 8% of the modern human genome. These retro...

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‘There and back again’: revisiting the pathophysiological roles of human endogenous retroviruses in the post-genomic era

Cited by 64 publications

References 154 publications

Mammalian Endogenous Retroviruses

Mammalian Endogenous Retroviruses

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences

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