HERV-K: The Biologically Most Active Human Endogenous Retrovirus Family

Tönjes, Ralf R.; Löwer, Roswitha; Boller, Klaus; Denner, Joachim; Hasenmaier, Brigitte; Kirsch, Heidrun; König, Herbert; Korbmacher, Christine; Limbach, Christiane; Lugert, Raimond; Phelps, Robert C.; Scherer, Jürgen; Thelen, K.; Löwer, Johannes; Kurth, Reinhard

doi:10.1097/00042560-199600001-00039

Cited by 78 publications

(70 citation statements)

References 40 publications

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“…The existence of a functional HERV-K protease was inferred from the presence of processed Gag proteins in teratocarcinoma cells (5). Direct evidence for a functional protease activity came from expression of different clones in E. coli (15,17,25,38).…”

Section: Discussionmentioning

confidence: 99%

“…The retroviral element that carries a primer binding site complementary to the 3Ј end of a lysine tRNA is called HERV-K. HERV type K represents the biologically most active form of a variety of retroviral elements present in the human genome (1,5). Although the HERV-K group comes closest of all known HERVs to containing infectious virus, no corresponding replication-competent virus has so far been described (1,3).…”

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confidence: 99%

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Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

Kuhelj¹,

Rizzo²,

Chang

et al. 2001

Journal of Biological Chemistry

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A full-length and C-terminally truncated version of human endogenous retrovirus (HERV)-K10 protease were expressed in Escherichia coli and purified to homogeneity. Both versions of the protease efficiently processed HERV-K10 Gag polyprotein substrate. HERV-K10 Gag was also cleaved by human immunodeficiency virus, type 1 (HIV-1) protease, although at different sites. To identify compounds that could inhibit protein processing dependent on the HERV-K10 protease, a series of cyclic ureas that had previously been shown to inhibit HIV-1 protease was tested. Several symmetric bisamides acted as very potent inhibitors of both the truncated and full-length form of HERV-K10 protease, in subnanomolar or nanomolar range, respectively. One of the cyclic ureas, SD146, can inhibit the processing of in vitro translated HERV-K10 Gag polyprotein substrate by HERV-K10 protease. In addition, in virus-like particles isolated from the teratocarcinoma cell line NCCIT, there is significant accumulation of Gag and Gag-Pol precursors upon treatment with SD146, suggesting the compound efficiently blocks HERV-K Gag processing in cells. This is the first report of an inhibitor able to block cell-associated processing of Gag polypeptides of an endogenous retrovirus.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

Kuhelj¹,

Rizzo²,

Chang

et al. 2001

Journal of Biological Chemistry

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“…The human endogenous retrovirus type K (HERV-K) family comprises 30-50 full-length members per haploid genome, among which several contain intact open reading frames (reviewed in Löwer et al, 1996;Tönjes et al, 1996). Intact elements are flanked by two long terminal repeats each approximately 1-kb in length providing the promoter and poly-adenylation signals respectively.…”

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confidence: 99%

DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas

et al. 1999

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Summary Since DNA methylation is considered an important mechanism for silencing of retroelements in the mammalian genome, hypomethylation in human tumours may lead to their reactivation. The methylation status of LINE-1 retroposons was determined in 73 samples of urinary bladder cancers, 34 specimens of renal cell carcinoma and in the corresponding normal tissues by Southern blot analysis. LINE-1 sequences were strongly methylated in normal tissues and were significantly hypomethylated in 69 (95%) urothelial carcinomas, but in none of the renal carcinomas. Hypomethylation in bladder cancers was independent of stage and tended to increase with grade. The methylation status of HERV-K proviral DNA in normal and transformed urothelial cells paralleled that of LINE-1 sequences (r 2 = 0.87). It was shown by ligation-mediated polymerase chain reaction that hypomethylation also extended to the LINE-1 promoter sequence located at the 5′-ends of full-length elements which is repressed by methylation in somatic tissues. Accordingly, full-length LINE-1 transcripts were detected by Northern blot analysis in two urothelial carcinoma cell lines. In contrast, transcripts from HERV-K proviruses were restricted to teratocarcinoma cell lines. Our data indicate that genome-wide DNA hypomethylation is an early change in urothelial carcinoma, but is absent from renal cell carcinoma. The coordinate changes of LINE-1 and HERV-K DNA methylation suggest that hypomethylation in urothelial cancer affects a variety of different retroelements to similar extents. We speculate that decreased methylation of LINE-1 retroelements, in particular, may contribute to genomic instability in specific human tumours such as urothelial carcinoma by rendering these normally repressed sequences competent for transcription and recombination.

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“…The basal transcriptional activity of human endogenous retroviruses varies in different human cell and tissue types, both for those viruses that have intact genes and for those with mutated cistrons (18)(19)(20)(21)(22)(23). It appears that expression depends upon individual host factors, like ethnicity (10,21,22,24), cell populations (18,25,26), and tissue types (27)(28)(29).…”

mentioning

confidence: 99%

“…It appears that expression depends upon individual host factors, like ethnicity (10,21,22,24), cell populations (18,25,26), and tissue types (27)(28)(29). Additionally, external stimuli, such as infections, viral transactivators, chemical exposures, cytokines, hormones, and inflammation, can induce expression of these proviruses (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46).…”

mentioning

confidence: 99%

Regulation of the Human Endogenous Retrovirus K (HML-2) Transcriptome by the HIV-1 Tat Protein

Gonzalez-Hernandez

Cavalcoli

Sartor

et al. 2014

J Virol

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Approximately 8% of the human genome is made up of endogenous retroviral sequences. As the HIV-1 Tat protein activates the overall expression of the human endogenous retrovirus type K (HERV-K) (HML-2), we used next-generation sequencing to determine which of the 91 currently annotated HERV-K (HML-2) proviruses are regulated by Tat. Transcriptome sequencing of total RNA isolated from Tat-and vehicle-treated peripheral blood lymphocytes from a healthy donor showed that Tat significantly activates expression of 26 unique HERV-K (HML-2) proviruses, silences 12, and does not significantly alter the expression of the remaining proviruses. Quantitative reverse transcription-PCR validation of the sequencing data was performed on Tattreated PBLs of seven donors using provirus-specific primers and corroborated the results with a substantial degree of quantitative similarity. IMPORTANCEThe expression of HERV-K (HML-2) is tightly regulated but becomes markedly increased following infection with HIV-1, in part due to the HIV-1 Tat protein.The findings reported here demonstrate the complexity of the genome-wide regulation of HERV-K (HML-2) expression by Tat. This work also demonstrates that although HERV-K (HML-2) proviruses in the human genome are highly similar in terms of DNA sequence, modulation of the expression of specific proviruses in a given biological situation can be ascertained using next-generation sequencing and bioinformatics analysis.

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HERV-K: The Biologically Most Active Human Endogenous Retrovirus Family

Cited by 78 publications

References 40 publications

Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas

Regulation of the Human Endogenous Retrovirus K (HML-2) Transcriptome by the HIV-1 Tat Protein

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