Multiple human endogenous retrovirus (HERV-K) loci with &lt;i&gt;gag&lt;/i&gt; open reading frames in the human genome

Mayer, Jens; Meese, Eckart; Mueller-Lantzsch, N.

doi:10.1159/000134614

Cytogenet Genome Res

1997

DOI: 10.1159/000134614

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Multiple human endogenous retrovirus (HERV-K) loci with <i>gag</i> open reading frames in the human genome

Jens Mayer

Eckart Meese

N. Mueller-Lantzsch³

Abstract: Human endogenous retrovirus HERV-K is present in 25–30 copies per haploid human genome. At least one of these loci is capable of producing full-length Gag protein, high amounts of which have been detected in germ cell tumors and derived cell lines. The latter display HERV-K Gag-encoded retroviral particles. Here, we employed the protein truncation test (PTT) in combination with a monochromosomal hybrid mapping panel to identify the human chromosomes harboring HERV-K gag genes with an open reading frame for Gag… Show more

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Cited by 33 publications

(21 citation statements)

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“…While no single human endogenous retrovirus sequence thus far identified in the genome encodes a complete infectious virus, the diverse HK2 loci in the human genome retain coding capacity for every functional retroviral protein (4,10,(28)(29)(30): the Gag protein, necessary for particle formation and release (31)(32)(33)(34)(35); the Pro protein, necessary for cleavage and maturation of viral proteins (35)(36)(37); the Pol protein, necessary for RNA-dependent DNA replication and integration (38)(39)(40)(41)(42); the accessory protein Rec, which exports unspliced viral RNA from the nucleus to the cytoplasm (43,44); and functional Env proteins (45). 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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mentioning

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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“…Among the HERVs, the betaretrovirus subgroup HERV-K/ HML-2 (HERV-K), is unique in the respect that several proviruses have retained open reading frames for some, if not all, retroviral proteins and are still able to form retrovirus-like particles (7,36,44,45). HERV-K is a complex retrovirus carrying, inter alia, the rec gene, encoding a nuclear RNA export adapter essential for the expression of the viral proteins (37).…”

mentioning

confidence: 99%

Expression of the Human Endogenous Retrovirus (HERV) Group HML-2/HERV-K Does Not Depend on Canonical Promoter Elements but Is Regulated by Transcription Factors Sp1 and Sp3

Fuchs

Kraft

Tondera

et al. 2011

J Virol

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After fixation in the human genome, human endogenous retroviruses (HERVs) are bona fide cellular genes despite their exogenous origin. To be able to spread within the germ line and the early embryo, the ancient retroviral promoters must have adapted to the requirements for expression in these cell types. We describe that in contrast to the case for current exogenous retroviruses, which replicate in specific somatic cells, the long terminal repeat (LTR) of the human endogenous retrovirus HERV-K acts as a TATA-and initiator elementindependent promoter with a variable transcription start site. We present evidence that the HERV-K LTR is regulated by the transcription factors Sp1 and Sp3. Mutating specific GC boxes, which are binding sites for Sp proteins, and knocking down Sp1 and Sp3 by use of small interfering RNA (siRNA) significantly reduced the promoter activity. Binding of Sp1 and Sp3 to the promoter region was confirmed using electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP). Our data explain why certain HERV-K proviruses have lost promoter competence. Since vertebrate promoters lacking canonical core promoter elements are common but poorly studied, understanding the HERV-K promoter not only will provide insight into the regulation of endogenous retroviruses but also can serve as a paradigm for understanding the regulation of this class of cellular genes.Human endogenous retroviruses (HERVs) bear witness that during primate/human evolution exogenous retroviruses have repetitively infected and colonized the germ lines of their respective hosts. HERV sequences constitute approximately 8% of the human genome. However, all present-day proviral loci in the human lineage are rendered noninfectious by mutations and deletions, probably through genetic drift and-given the mutagenic potential of retroviruses-selection for replicationincompetent proviruses. In addition, detailed in silico analyses showed that several HERV proviruses are already inactivated during the primary infection cycle by an APOBEC3G cytosine deaminase, an antiretroviral gene which leaves specific mutation marks within the proviral DNA (17, 33).

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“…First, despite their long-time presence in the human genome, a number of proviruses still display open reading frames for retroviral Gag, Prt, Pol, and/or Env proteins (3,4,29,30,40). Second, transcriptional activity of the HERV-K(HML-2) family is strongly upregulated in human germ cell tumors (GCTs) and GCT-derived cell lines, as opposed to transcriptional silencing in non-GCT cell lines.…”

mentioning

confidence: 99%

CpG Methylation Directly Regulates Transcriptional Activity of the Human Endogenous Retrovirus Family HERV-K(HML-2)

Lavie

Kitova

Maldener

et al. 2005

J Virol

192

150

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Multiple human endogenous retrovirus (HERV-K) loci with <i>gag</i> open reading frames in the human genome

Cited by 33 publications

References 11 publications

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

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

Expression of the Human Endogenous Retrovirus (HERV) Group HML-2/HERV-K Does Not Depend on Canonical Promoter Elements but Is Regulated by Transcription Factors Sp1 and Sp3

CpG Methylation Directly Regulates Transcriptional Activity of the Human Endogenous Retrovirus Family HERV-K(HML-2)

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