HERV-K(HML-2), the Best Preserved Family of HERVs: Endogenization, Expression, and Implications in Health and Disease
Open accessAbstract
Retroviruses that have the ability to infect germ line cells can become an integral and inherited part of the host genome. About 8% of the human chromosomal DNA consists of sequences derived from infections by retroviruses that presumably circulated 2-40 millions of years ago, and some elements are actually much older. Post-insertional recombinations, deletions, and mutations have rendered all known human endogenous retroviruses (HERVs) non-infectious. However some, particularly the most recently acquired proviruses of the HERV-K(HML-2) family, can expresses viral proteins and produce viral particles. In this review we will first discuss the major aspects of the endogenization process and peculiarities of the different HERV-K families. We will then focus on the genes and proteins encoded by HERV-K(HML-2) as well as inactivation of these proviruses by postinsertional mutations and their inhibition by antiretroviral factors. After describing the evolutionary interplay between host and endogenous retrovirus we will delve deeper into the currently limited understanding of HERV-K and its possible association with disease, particularly tumorigenesis.
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Each of the viral genes are functional in at least one provirus in the genome, providing for the possibility that partially functional viral particles may be produced, or that functional viral particles could be generated by trans-complementation.
“Each of the viral genes are functional in at least one provirus in the genome, providing for the possibility that partially functional viral particles may be produced, or that functional viral particles could be generated by trans-complementation.”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Hohn et al. 2013
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredAlthough there are no replication-competent human endogenous retroviruses (HERVs), the human genome contains a number of full-length HERV-K(HML-2) proviruses that each encode several intact open reading frames.
“Although there are no replication-competent human endogenous retroviruses (HERVs), the human genome contains a number of full-length HERV-K(HML-2) proviruses that each encode several intact open reading frames”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Hohn et al. 2013
The Introduction says all known human proviruses are non-infectious, and the Postintegrational Mutations and Replication Potential of HERV-K section describes HERV-K(HML-2) proviruses with open reading frames for all viral genes. But that section does not rule out an infectious HERV-K(HML-2) provirus of low prevalence, so the claim's unqualified statement that none are replication-competent is stronger than the source. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThere is no fully functional HERV-K in the human genome, but a number of HERV-K proviruses are capable of making one or several of the viral proteins.
“There is no fully functional HERV-K in the human genome, but a number of HERV-K proviruses are capable of making one or several of the viral proteins”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Hohn et al. 2013
The Introduction says many HERV-K(HML-2) proviruses retain open reading frames for functional viral proteins. The Postintegrational Mutations and Replication Potential section says no currently known HERV-K(HML-2) element appears able to produce infectious particles, but it does not rule out a rare infectious provirus. The claim makes that qualified finding categorical and extends it from HML-2 to all HERV-K. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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“HERV-K specific CD8+ T-cells that can recognize and kill cells presenting the cognate peptides as a result of HIVinduced expression of HERV proteins (119) may play an important part in the natural immune response to HIV (121).”
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BackgroundHuman endogenous retroviruses and multiple sclerosis: Innocent bystanders or disease determinants?
Antony, J. M., Deslauriers, A. M., Bhat, R. K., Ellestad, K. K., & Power, C. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.07.016 · Cited by 127 · cited 1× · see citing works
“However, Moyes and Colleagues have published data showing that HERV-K113 and HERV-K115 are not significantly increased in patients with MS compared to the combined parent group (79, 80) and their results do not therefore support an association between these particular endogenous retroviruses and MS (79, 81).”
ResultSpencer, T. E., Mura, M., Gray, C., Griebel, P. J., & Palmarini, M. (2003) · Journal of Virology · doi:10.1128/jvi.77.1.749-753.2003 · Cited by 126 · cited 3× · see citing works
“Furthermore, the Gag protein of defective transdominant endogenous JSRV interferes at a late stage of replication with the exogenous form of the protein (66), a phenomenon also described in mice in which expression of an endogenous retroviral Gag protein with homology to the HERV-L family blocks various strains of exo…”
BackgroundChen, T., Meng, Z., Gan, Y., Wang, X., Xu, F., Gu, Y., Xu, X., Tang, J., Zhou, H., Zhang, X., et al. (2013) · Leukemia · doi:10.1038/leu.2013.8 · Cited by 126 · cited 2× · see citing works
“Furthermore, Chen and Co-workers recently reported that Np9 is a potent viral oncogene in human leukemia (145).”
BackgroundBüscher, K., Hahn, S., Hofmann, M. A., Trefzer, U., Özel, M., Sterry, W., Löwer, J., Löwer, R., Kurth, R., & Denner, J. (2006) · Melanoma Research · doi:10.1097/01.cmr.0000215031.07941.ca · Cited by 125 · see citing works
Boese, A. S., Sauter, M., Galli, U., Best, B. A., Herbst, H., Mayer, J. M., Kremmer, E., Roemer, K., & Müeller, A. (2000) · Oncogene · doi:10.1038/sj.onc.1203794 · Cited by 125 · see citing works
Expression of Human Endogenous Retrovirus Type K (HML-2) Is Activated by the Tat Protein of HIV-1
Gonzalez-Hernandez, M. J., Swanson, M. D., Contreras-Galindo, R., Cookinham, S., King, S. R., Noel, R. J., Kaplan, M. H., & Markovitz, D. M. (2012) · Journal of Virology · doi:10.1128/jvi.07215-11 · Cited by 123 · see citing works
Galli, U. M., Sauter, M., Lecher, B., Maurer, S., Herbst, H., Roemer, K., & Mueller-Lantzsch, N. (2005) · Oncogene · doi:10.1038/sj.onc.1208543 · Cited by 120 · cited 1× · see citing works
“In 2005, Galli and Co-workers demonstrated that transgenic mice expressing Rec show disturbances in germ cell development and that some animals develop lesions similar to the predecessor lesions of classical seminomas in humans (138).”
BackgroundNotch Signaling in Mammary Gland Tumorigenesis
Callahan, R., & Raafat, A. (2004) · Journal of mammary gland biology and neoplasia · doi:10.1023/a:1009512414430 · Cited by 120
Measuring Fertility with the 1901 Canadian Census: A Critical Assessment
Gauvreau, D., Gossage, P., & Gingras, L. (2000) · Historical Methods · doi:10.1080/01615440009598964 · Cited by 118 · cited 1×
“The simple insertion of an LTR can replace the original promoter, alter tissue specificity, or add enhancer activity (16).”
Palmarini, M., Mura, M., & Spencer, T. (2004) · Journal of General Virology · doi:10.1099/vir.0.19547-0 · Cited by 118 · cited 1× · see citing works
“Human endogenous retroviruses and multiple sclerosis: innocent bystanders or disease determinants? Biochim Biophys Acta (2011) 1812(2):162–76.”
BackgroundGenetic transmission of viruses that incite mammary tumor in mice.
Bentvelzen, P., Daams, J., Hageman, P., & Calafat, J. (1970) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.67.1.377 · Cited by 116 · cited 3×
“Proc Natl Acad Sci U S A (1970) 67(1):377–84.”
InfluentialFreimanis, G., Hooley, P., Ejtehadi, H. D., Ali, H. A., Veitch, A. M., Rylance, P. B., Alawi, A., Axford, J. S., Nevill, A. M., Murray, P. G., et al. (2010) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2010.04110.x · Cited by 116 · see citing works
Potential mechanisms of endogenous retroviral-mediated genomic instability in human cancer
Romanish, M. T., Cohen, C., & Mager, D. L. (2010) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2010.05.005 · Cited by 113 · cited 1× · see citing works
“Recombination involving HERV-K sequences might also lead to chromosomal instability and large-scale chromosomal anomalies such as those typically observed in aberrant cells (131, 132).”
BackgroundLavie, L., Maldener, E., Brouha, B., Meese, E. U., & Mayer, J. M. (2004) · Genome Research · doi:10.1101/gr.2745804 · Cited by 113 · cited 1× · see citing works
“However, sequence comparisons show that HML-5 does not lie at the root of the HERV-K phylogenetic tree, suggesting that this is probably not the case (40).”
BackgroundTranscriptional Profiling of Human Endogenous Retrovirus Group HERV-K(HML-2) Loci in Melanoma
Schmitt, K., Reichrath, J., Roesch, A., Meese, E. U., & Mayer, J. M. (2013) · Genome Biology and Evolution · doi:10.1093/gbe/evt010 · Cited by 112 · see citing works
Human Endogenous Retrovirus (HERV-K) Reverse Transcriptase as a Breast Cancer Prognostic Marker
Golan, M., Hizi, A., Resau, J. H., Yaal‐Hahoshen, N., Reichman, H., Keydar, I., & Tsarfaty, I. (2008) · Neoplasia · doi:10.1593/neo.07986 · Cited by 109 · cited 4× · see citing works
“It is interesting that HERV-K transcription (and subsequently Rec expression) can be stimulated by hormones, including androgens, and various steroid hormone-binding sites are predicted to be located within the HERV-K LTR (89, 93, 95, 113).”
BackgroundInfluentialHahn, S., Ugurel, S., Hanschmann, K.-M. O., Strobel, H., Tondera, C., Schadendorf, D., Löwer, J., & Löwer, R. (2008) · AIDS Research and Human Retroviruses · doi:10.1089/aid.2007.0286 · Cited by 109 · cited 2× · see citing works
“showed in 2008 that the immune response of melanoma patients against HERVK gene products correlates negatively with their survival (106).”
BackgroundHuman cis natural antisense transcripts initiated by transposable elements
Conley, A. B., Miller, W. J., & Jordan, I. K. (2008) · Trends in Genetics · doi:10.1016/j.tig.2007.11.008 · Cited by 108 · cited 1× · see citing works
“The transcripts induced include many RNAs that are complementary to regular gene transcripts and can downregulate the expression of cellular genes (17).”
BackgroundThe distribution of the endogenous retroviruses HERV-K113 and HERV-K115 in health and disease.
Moyes, D., Martín, A., Sawcer, S., Temperton, N. J., Worthington, J., Griffiths, D. J., & Venables, P. (2005) · Genomics · doi:10.1016/j.ygeno.2005.06.004 · Cited by 105 · cited 1× · see citing works
“However, Moyes and Colleagues have published data showing that HERV-K113 and HERV-K115 are not significantly increased in patients with MS compared to the combined parent group (79, 80) and their results do not therefore support an association between these particular endogenous retroviruses and MS (79, 81).”
ResultBuzdin, A. A., Alexandrova, E., Gogvadze, E. V., & Sverdlov, E. D. (2006) · Journal of Virology · doi:10.1128/jvi.00871-06 · Cited by 104 · cited 1× · see citing works
“number of known genes that are under definite transcriptional control by HERVs and our understanding of the mechanisms involved have dramatically increased in recent years (14).”
BackgroundCharacterization of Human Endogenous Retroviral Elements in the Blood of HIV-1-Infected Individuals
Contreras-Galindo, R., Kaplan, M. H., Contreras-Galindo, A. C., Gonzalez-Hernandez, M. J., Ferlenghi, I., Giusti, F., Lorenzo, E., Gitlin, S. D., Dosik, M. H., Yamamura, Y., et al. (2012) · Journal of Virology · doi:10.1128/jvi.00602-11 · Cited by 103 · cited 1× · see citing works
“Subsequently, it was even possible to observe virus-like particles by electron microscopy and by immunostaining using HERV-K Env and Gag specific antibodies (116).”
BackgroundKrone, B., Kölmel, K., Henz, B., & Grange, J. (2005) · European Journal of Cancer · doi:10.1016/j.ejca.2004.08.010 · Cited by 102 · see citing works
Detection of HERV-K(HML-2) Viral RNA in Plasma of HIV Type 1-Infected Individuals
Contreras-Galindo, R., Kaplan, M. H., Markovitz, D. M., Lorenzo, E., & Yamamura, Y. (2006) · AIDS Research and Human Retroviruses · doi:10.1089/aid.2006.22.979 · Cited by 101 · see citing works
Hypermutation of an Ancient Human Retrovirus by APOBEC3G
Lee, Y. N., Malim, M. H., & Bieniasz, P. D. (2008) · Journal of Virology · doi:10.1128/jvi.00751-08 · Cited by 98 · cited 2× · see citing works
“HERV-K(HML-2) is particularly susceptible to APOBEC 3F and APOBEC 3G deamination as shown in infectivity assays using infectious viruses produced with HERV-K(HML-2) consensus sequences (9, 53).”
BackgroundHuman teratocarcinomas cultured in vitro produce unique retrovirus-like viruses.
Löwer, R., Löwer, J., Frank, H., Harzmann, R., & Kurth, R. (1984) · Journal of General Virology · doi:10.1099/0022-1317-65-5-887 · Cited by 96 · cited 1× · see citing works
“AIDS Res Hum Retroviruses (2008) 24(5):717–23.”
Seifarth, W., Baust, C., Murr, A., Skladny, H., Krieg-Schneider, F., Blusch, J., Werner, T., Hehlmann, R., & Leib‐Mösch, C. (1998) · Journal of Virology · doi:10.1128/jvi.72.10.8384-8391.1998 · Cited by 95 · cited 2× · see citing works
“Searching for sequences derived from the cloned HERV-K (HML-1 to HML-10) elements reveals a probable total of about 550 HERV-K proviruses and 6400 solitary LTRs in the human genome (36), ranging from 150 HML-3 proviral elements to 5 HML-4 proviruses, for example (24, 37).”
BackgroundSjøttem, E., Anderssen, S., & Johansen, T. (1996) · Journal of Virology · doi:10.1128/jvi.70.1.188-198.1996 · Cited by 94 · see citing works
HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates
Jones, R. B., Garrison, K. E., Mujib, S., Mihajlovic, V., Aidarus, N., Hunter, D. V., Martin, E., John, V. M., Zhan, W., Faruk, N. F., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci64560 · Cited by 91 · cited 1× · see citing works
“Having an unchanging target allows HERV-specific T-cell clones from HIV-1 infected individuals to kill, in vitro at least, human CD4+ cells infected with viruses as diverse as HIV-1, HIV-2, and SIV (122).”
BackgroundNp9 Protein of Human Endogenous Retrovirus K Interacts with Ligand of Numb Protein X
Armbruester, V., Sauter, M., Roemer, K., Best, B. A., Hahn, S., Nty, A., Schmid, A., Philipp, S. E., Müeller, A., & Mueller‐Lantzsch, N. (2004) · Journal of Virology · doi:10.1128/jvi.78.19.10310-10319.2004 · Cited by 91 · cited 1× · see citing works
“Np9 has also been shown to interact with the ligand of Numb protein X (LNX), a RING-type E3 ubiquitin ligase that ubiquitylates Numb and marks it for degradation by 26S proteasomes (146).”
BackgroundAllelic Variation of HERV-K(HML-2) Endogenous Retroviral Elements in Human Populations
Macfarlane, C. M., & Peter Simmonds, K. (2004) · Journal of Molecular Evolution · doi:10.1007/s00239-004-2656-1 · Cited by 89 · cited 3× · see citing works
“Only type II proviruses express the accessory Rec protein that functionally resembles the HIV Rev and HTLV Rex proteins (10, 11).”
BackgroundDevelopmental expression of HERV-R (ERV3) and HERV-K in human tissue.
Andersson, A., Venables, P., Tonjes, R., Scherer, J., Eriksson, L., & Larsson, E. (2002) · Virology · doi:10.1006/viro.2002.1428 · Cited by 89 · cited 1× · see citing works
“Andersson and Colleagues made the very interesting discovery of HERV-K rec transcripts in the placenta and in various other normal human fetal tissues, suggesting that this small RNA transport molecule may play a role in the development and differentiation of human tissues (73).”
BackgroundBuchanan, G., Ricciardelli, C., Harris, J. M., Prescott, J., Yu, Z. C.-L., Li, J., Butler, L. M., Marshall, V. R., Scher, H. I., Gerald, W. L., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1646 · Cited by 86 · cited 1× · see citing works
“Rec interacts directly with the human small glutamine-rich tetratricopeptide repeat-containing protein (hSGT), a co-chaperone and negative regulator of the AR (93, 144).”
BackgroundWeiss, R. A., & Payne, L. N. (1971) · Virology · doi:10.1016/0042-6822(71)90351-5 · Cited by 85 · cited 2× · see citing works
“Proc Natl Acad Sci U S A (2003) 100(22):13013–8.”
Schlecht-Louf, G., Renard, M., Mangeney, M., Letzelter, C., Richaud, A., Ducos, B., Bouallaga, I., & Heidmann, T. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913122107 · Cited by 84 · cited 1× · see citing works
“Furthermore, the envelope proteins are involved in retrovirus-induced immunosuppression (61) and as the placenta, as far as the mother’s immune system is concerned, is an allogeneic organ, local immunological tolerance is necessary to prevent rejection of the fetus.”
BackgroundHuman endogenous retrovirus-K18 Env as a risk factor in multiple sclerosis
Tai, A., O’Reilly, É., Alroy, K., Simon, K., Munger, K. L., Huber, B. T., & Ascherio, A. (2008) · Multiple Sclerosis Journal · doi:10.1177/1352458508094641 · Cited by 82 · cited 1× · see citing works
“Indeed, Tai and Colleagues found HERV-K18 expressing a superantigen in its env gene to be a risk factor for MS (76) and although this observation was made in a very small cohort, it is exciting because expression of HERV-K18 superantigen is also elevated in juvenile RA (77).”
BackgroundKämmerer, U., Germeyer, A., Stengel, S., Kapp, M., & Denner, J. (2011) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2011.06.102 · Cited by 81 · cited 1× · see citing works
“subunit in placental cytotrophoblast cells suggests its potential involvement in placentogenesis and pregnancy (71), as discussed above for syncytin-1 and -2.”
BackgroundHuman-Specific Modulation of Transcriptional Activity Provided by Endogenous Retroviral Insertions
Gogvadze, E. V., Stukacheva, E. A., Buzdin, A. A., & Sverdlov, E. D. (2009) · Journal of Virology · doi:10.1128/jvi.00123-09 · Cited by 80 · see citing works
Diversity of human endogenous retrovirus class II-like sequences.
Andersson, M.-L., Lindeskog, M., Medstrand, P., Westley, B., May, F., & Blomberg, J. (1999) · Journal of General Virology · doi:10.1099/0022-1317-80-1-255 · Cited by 79 · cited 1× · see citing works
“These results were subsequently compiled to yield our current understanding that there are up to 10 HERV-K(HML) families in addition to a related family HERV-K(14C) present in the human genome (35).”
BackgroundEvidence for Viral Etiology of Multiple Sclerosis
Tselis, A. (2011) · Seminars in neurology · doi:10.1055/s-0031-1287656 · Cited by 78 · cited 1× · see citing works
“One interesting hypotheses involves a neurotropic infectious agent, possibly a virus, and HERV-K(HML-2) is one candidate in this context (75).”
BackgroundHuman endogenous retroviruses and cancer prevention: evidence and prospects
Cegolon, L., Salata, C., Weiderpass, E., Vineis, P., Palù, G., & Mastrangelo, G. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-4 · Cited by 77 · see citing works
Contreras-Galindo, R., González, M., Almodóvar-Camacho, S., González-Ramírez, S., Lorenzo, E., & Yamamura, Y. (2006) · Journal of Virological Methods · doi:10.1016/j.jviromet.2006.03.029 · Cited by 76 · see citing works
Hayashi, T., Kageyama, Y., Ishizaka, K., Xia, G., Kihara, K., & Oshima, H. (2001) · Journal of Andrology · doi:10.1002/j.1939-4640.2001.tb03441.x · Cited by 76 · see citing works
Mager, D. L., & Medstrand, P. (2005) · Encyclopedia of Life Sciences · doi:10.1038/npg.els.0005062 · Cited by 73 · see citing works
Association of human endogenous retrovirus K-18 polymorphisms with type 1 diabetes.
Marguerat, S., Wang, W. Y. S., Todd, J., & Conrad, B. (2004) · Diabetes · doi:10.2337/diabetes.53.3.852 · Cited by 73 · cited 1× · see citing works
“Finally, various groups have reported an association between HERV-K18 polymorphisms and type 1 diabetes (82, 83).”
BackgroundHuman endogenous retroviruses in the primate lineage and their influence on host genomes
Mayer, J. M., & Meese, E. U. (2005) · Cytogenetic and Genome Research · doi:10.1159/000084977 · Cited by 72 · cited 2× · see citing works
“Searching for sequences derived from the cloned HERV-K (HML-1 to HML-10) elements reveals a probable total of about 550 HERV-K proviruses and 6400 solitary LTRs in the human genome (36), ranging from 150 HML-3 proviral elements to 5 HML-4 proviruses, for example (24, 37).”
BackgroundGotzinger, N., Sauter, M., Roemer, K., & Mueller-Lantzsch, N. (1996) · Journal of General Virology · doi:10.1099/0022-1317-77-12-2983 · Cited by 72 · cited 1× · see citing works
“In this regard it should be stressed that transcription of HERVK and other HERV elements is usually suppressed by epigenetic factors such as DNA methylation and heterochromatin-silencing by histone modifications (15).”
BackgroundLee, W.-J., Kwun, H., Kim, H. S., & Jang, K. (2003) · Molecules and Cells · doi:10.1016/s1016-8478(23)13710-1 · Cited by 71 · see citing works
Kaufmann, S. H., Sauter, M., Schmitt, M., Baumert, B., Best, B. A., Boese, A. S., Roemer, K., & Müeller, A. (2010) · Journal of General Virology · doi:10.1099/vir.0.014241-0 · Cited by 70 · cited 1× · see citing works
“reported that Rec forms trimeric complexes with the testicular zinc-finger protein (TZFP) and the AR (143).”
BackgroundHERV‐K(HML‐2) GAG/ENV antibodies as indicator for therapy effect in patients with germ cell tumors
Kleiman, A., Senyuta, N., Tryakin, A., Sauter, M., Karseladze, A., Tjulandin, S., Gurtsevitch, V., & Mueller-Lantzsch, N. (2004) · International Journal of Cancer · doi:10.1002/ijc.11649 · Cited by 70 · cited 1× · see citing works
“The presence of antibodies specific for HERV-K(HML2) proteins correlates strongly with the clinical manifestation of GCTs and may therefore be used as a diagnostic and prognostic marker for these types of cancer (92).”
BackgroundExpression of human sequences related to those of mouse mammary tumor virus
Franklin, G., Chretien, S., Hanson, I., Rochefort, H., May, F., & Westley, B. (1988) · Journal of Virology · doi:10.1128/jvi.62.4.1203-1210.1988 · Cited by 70 · cited 3× · see citing works
“Elements such as HML-4 and HML-6, which are related to but clearly distinct from the HERV-K(HML-2) prototype virus HERV-K10 (32), were identified more than 20 years ago by extensive lab work using low-stringency Southern blot analyses with MMTVderived gag/pol probes (33).”
BackgroundTassabehji, M., Strachan, T., Anderson, M., Campbell, R., Collier, S., & Lako, M. (1994) · Nucleic Acids Research · doi:10.1093/nar/22.24.5211 · Cited by 69 · see citing works
Endogenous Retrovirus Expression Is Required for Murine Melanoma Tumor Growth In vivo
Mangeney, M., Pothlichet, J., Renard, M., Ducos, B., & Heidmann, T. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-4231 · Cited by 68 · see citing works
SenGupta, D., Tandon, R., Vieira, R. G. S., Ndhlovu, L., Lown-Hecht, R., Ormsby, C., Loh, L., Jones, R., Garrison, K. E., Martin, J. N., et al. (2011) · Journal of Virology · doi:10.1128/jvi.00179-11 · Cited by 67 · cited 11×
“Division for HIV and Other Retroviruses, Robert Koch Institute, Berlin, Germany Edited by: Iyoko Katoh, University of Yamanashi, Japan Reviewed by: Holger Kalthoff, Institute for Experimental Cancer Research, Germany Shashidhar Jatiani, Forest Research Institute, USA *Correspondence: Norbert Bannert , Division for HIV…”
BackgroundInfluentialHanke, K., Chudak, C., Kurth, R., & Bannert, N. (2012) · International Journal of Cancer · doi:10.1002/ijc.27693 · Cited by 67 · cited 5× · see citing works
“Interestingly, HERV-K expression in teratocarcinoma cell lines can be further enhanced by androgens (93), although, it is still unknown whether the androgen receptor (AR) binds directly to HERV-K LTRs or acts via other host proteins.”
BackgroundInfluentialSelf-citationIramaneerat, K., Rattanatunyong, P., Khemapech, N., Triratanachat, S., & Mutirangura, A. (2010) · International Journal of Gynecologic Cancer · doi:10.1097/igc.0b013e3182021c1a · Cited by 66 · see citing works
Evidence of selection on the domesticated ERVWE1 env retroviral element involved in placentation.
Bonnaud, B., Bouton, O., Oriol, G., Cheynet, V., Duret, L., & Mallet, F. (2004) · Molecular biology and evolution · doi:10.1093/molbev/msh206 · Cited by 62 · cited 1× · see citing works
“In contrast, there are only very few elements that are obviously under strong positive selective pressure, none of which belong to the HERV-K(HML-2) family (30).”
BackgroundReiche, J., Pauli, G., & Ellerbrok, H. (2010) · Melanoma Research · doi:10.1097/cmr.0b013e32833c1b5d · Cited by 60 · cited 2× · see citing works
“In line with existing knowledge about melanoma development, HERV-K expression can be triggered by UV radiation and may therefore be able to accelerate carcinogenesis (107, 108).”
BackgroundKnössl, M., Löwer, R., & Löwer, J. (1999) · Journal of Virology · doi:10.1128/jvi.73.2.1254-1261.1999 · Cited by 60 · cited 1× · see citing works
“Direct binding of other cellular proteins and transcription factors to the HERV-K(HML-2) LTR have already been demonstrated (94, 95).”
BackgroundMicroarray-Based Sketches of the HERV Transcriptome Landscape
Pérot, P., Mugnier, N., Montgiraud, C., Gimenez, J., Jaillard, M., Bonnaud, B., & Mallet, F. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040194 · Cited by 59 · cited 2× · see citing works
“In particular, the testes and placenta appear to be privileged tissues for HERV expression (69).”
BackgroundMolecular cloning and functional characterization of the human endogenous retrovirus K113
Beimforde, N., Hanke, K., Ammar, I., Kurth, R., & Bannert, N. (2008) · Virology · doi:10.1016/j.virol.2007.09.036 · Cited by 54 · cited 1× · see citing works
“However, post-insertional mutations other than those that generate premature stop codons have since rendered these viruses replication incompetent (36, 54): infection could not be achieved using supernatants from germ line cells that”
BackgroundSelf-citationExpression of human endogenous retrovirus K is stimulated by ultraviolet radiation in melanoma
Schanab, O., Humer, J., Gleiß, A., Mikula, M., Šturlan, S., Grunt, S., Okamoto, I., Muster, T., Pehamberger, H., & Waltenberger, A. (2011) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2011.00860.x · Cited by 52 · cited 1× · see citing works
“In line with existing knowledge about melanoma development, HERV-K expression can be triggered by UV radiation and may therefore be able to accelerate carcinogenesis (107, 108).”
BackgroundHanke, K., Krämer, P., Seeher, S., Beimforde, N., Kurth, R., & Bannert, N. (2009) · Journal of Virology · doi:10.1128/jvi.01368-09 · Cited by 46 · cited 1× · see citing works
“A functional Env protein has only been described for the HERVK108 provirus (50), although the infectivity of another HERVK(HML-2) element (K113) could be restored by back mutation of putative post-insertional amino acid changes (51).”
BackgroundSelf-citationThe Human Endogenous Retrovirus Family HERV-K(HML-3)
Mayer, J. M., & Meese, E. U. (2002) · Genomics · doi:10.1006/geno.2002.6839 · Cited by 45 · cited 1× · see citing works
“and Meese (43) HML-4 HERVK13I, HERV-K-T47D ∼55–35 5 800 Medstrand and Blomberg (34), Seifarth et al.”
BackgroundConstruction and Characterization of an Infectious Molecular Clone of Koala Retrovirus
Shojima, T., Hoshino, S., Abe, M., Yasuda, J., Shogen, H., Kobayashi, T., & Miyazawa, T. (2013) · Journal of Virology · doi:10.1128/jvi.01584-12 · Cited by 42 · cited 1×
“Proc Natl Acad Sci U S A (2009) 106(29):12127–32.”
The role of human endogenous retroviruses in melanoma
Singh, S., Kaye, S., Gore, M. E., McClure, M. O., & Bunker, C. B. (2009) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2009.09415.x · Cited by 41 · see citing works
Methods for estimating human endogenous retrovirus activities from EST databases
Oja, M., Peltonen, J., Blomberg, J., & Kaski, S. (2007) · BMC Bioinformatics · doi:10.1186/1471-2105-8-s2-s11 · Cited by 40 · cited 1×
“Various groups have found that between 7 and 30% of all HERV sequences in the genome are transcriptionally active (18, 68, 69).”
BackgroundStructure and genomic organization of a novel human endogenous retrovirus family: HERV-K (HML-6).
Medstrand, P., Yin, H., Mager, D. L., Blomberg, J., & Dietrich, U. (1997) · Journal of General Virology · doi:10.1099/0022-1317-78-7-1731 · Cited by 38 · see citing works
Flockerzi, A., Burkhardt, S., Schempp, W., Meese, E., & Mayer, J. (2005) · Journal of Virology · doi:10.1128/jvi.79.5.2941-2949.2005 · Cited by 38 · cited 1×
“Remarkably, within the HML-1 family seven proviruses were found in which gag, pro, and pol sequences have been replaced by similar regions from HERV-W, resulting in hybrid structures (41).”
Backgroundde Parseval, N., Alkabbani, H., & Heidmann, T. (1999) · Journal of General Virology · doi:10.1099/0022-1317-80-4-841 · Cited by 37
Adamah, D., Gokhale, P., Eastwood, D. J., De-Meyts, E. R., Goepel, J., Walsh, J., Moore, H., & Andrews, P. (2006) · International Journal of Andrology · doi:10.1111/j.1365-2605.2005.00569.x · Cited by 34 · see citing works
Human endogenous retroviruses and cancer: Causality and therapeutic possibilities
Mullins, C. S. (2012) · World Journal of Gastroenterology · doi:10.3748/wjg.v18.i42.6027 · Cited by 34 · see citing works
Febrile infections and malignant melanoma: results of a case-control study.
Kölmel, K., Gefeller, O., & Haferkamp, B. (1992) · Melanoma research · doi:10.1097/00008390-199209000-00009 · Cited by 33
A novel multiplex RT-PCR system detects human endogenous retrovirus-K in breast cancer
Ejthadi, H. D., Martin, J., Junying, J., Roden, D., Lahiri, M., Warren, P., Murray, P., & Nelson, P. N. (2004) · Archives of Virology · doi:10.1007/s00705-004-0378-8 · Cited by 33 · see citing works
HERV-K113 Is Not Associated with Multiple Sclerosis in a Large Family-Based Study
Moyes, D. L., Goris, A., Ban, M., Compston, A., Griffiths, D. J., Sawcer, S. J., & Venables, P. J. (2008) · AIDS Research and Human Retroviruses · doi:10.1089/aid.2007.0196 · Cited by 33 · cited 1× · see citing works
“However, Moyes and Colleagues have published data showing that HERV-K113 and HERV-K115 are not significantly increased in patients with MS compared to the combined parent group (79, 80) and their results do not therefore support an association between these particular endogenous retroviruses and MS (79, 81).”
ResultGeorge, M., Schwecke, T., Beimforde, N., Höhn, O., Chudak, C., Zimmermann, A., Kurth, R., Naumann, D., & Bannert, N. (2011) · Retrovirology · doi:10.1186/1742-4690-8-30 · Cited by 32 · cited 1× · see citing works
“The full-length HML-2 mRNA encodes the structural proteins of Gag, termed matrix (MA, p15), capsid (CA, p27), nucleocapsid (NC, p10) plus three smaller peptides as well as the putative phosphoprotein (pp15) (49).”
BackgroundSelf-citationPresence of dUTPase in the Various Human Endogenous Retrovirus K (HERV-K) Families
Mayer, J., & Meese, E. (2003) · Journal of Molecular Evolution · doi:10.1007/s00239-003-2514-6 · Cited by 27 · cited 1× · see citing works
“, Maedi-Visna virus (MVV) and equine infectious anemia virus (EIAV)] feature a dUTPase, albeit located in different regions of the genome (31, 52).”
BackgroundYin, H., Medstrand, P., Kristofferson, A., Dietrich, U., Åman, P., & Blomberg, J. (1999) · Virology · doi:10.1006/viro.1998.9587 · Cited by 27
Hirschl, S., Schanab, O., Seppele, H., Waltenberger, A., Humer, J., Wolff, K., Pehamberger, H., & Muster, T. (2007) · Virus Research · doi:10.1016/j.virusres.2006.08.010 · Cited by 21 · see citing works
Hayashi, T., Yamada, T., Kageyama, Y., & Kihara, K. (2004) · Tumor Biology · doi:10.1159/000079140 · Cited by 18
Jones, R., Leal, F., Hasenkrug, A. M., Segurado, A., Nixon, D. F., Ostrowski, M., & Kallas, E. (2013) · Journal of Negative Results in Biomedicine · doi:10.1186/1477-5751-12-3 · Cited by 14 · see citing works
Can prior vaccinations against certain infections confer protection against developing melanoma?
Grange, J., Krone, B., Kölmel, K., & Mastrangelo, G. (2009) · Medical Journal of Australia · doi:10.5694/j.1326-5377.2009.tb02907.x · Cited by 9
Endogenous Retroviruses and Cancer
Dudley, J. P., Mertz, J. A., Bhadra, S., Palmarini, M., & Kozak, C. A. (2010) · Springer eBooks · doi:10.1007/978-0-387-09581-3_5 · Cited by 8 · cited 1× · see citing works
“A second mechanism of tumor induction/promotion by HERV-K is the inactivation of tumor suppressor genes by de novo insertion or translocation of retroelements within the genome (70, 130).”
Background
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22 of the 166 references couldn’t be matched to a known paper.
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Cited by
Sorted by citations
Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells
Grow, E. J., Flynn, R. A., Chavez, S. L., Bayless, N. L., Wossidlo, M., Wesche, D. J., Martin, L., Ware, C. B., Blish, C. A., Chang, H. Y., et al. (2015) · Nature · doi:10.1038/nature14308 · Cited by 647 · see citing works
Historical review of the causes of cancer
Blackadar, C. B. (2016) · World Journal of Clinical Oncology · doi:10.5306/wjco.v7.i1.54 · Cited by 394 · see citing works
Discovery of unfixed endogenous retrovirus insertions in diverse human populations
Halo, J. V., Williams, Z. H., Montesion, M., Subramanian, R. P., Kidd, J. M., & Coffin, J. M. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1602336113 · Cited by 280 · see citing works
“This expression has been shown to exhibit tissue specificity in the form of proviral RNAs from both type 1 and 2 proviruses that have no apparent match to annotated loci (16, 17), implying the presence of transcriptionally active but not yet characterized loci.”
BackgroundDefective HIV-1 proviruses produce viral proteins
Imamichi, H., Smith, M., Adelsberger, J. W., Izumi, T., Scrimieri, F., Sherman, B. T., Rehm, C. A., Imamichi, T., Pau, A., Catalfamo, M., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1917876117 · Cited by 251 · see citing works
Endogenous retroviral promoter exaptation in human cancer
Babaian, A., & Mager, D. L. (2016) · Mobile DNA · doi:10.1186/s13100-016-0080-x · Cited by 248 · see citing works
“HERV-H/LTR7-driven RNAs in pluripotency [56–58, 60, 179, 180] or on the youngest HERV group, HERV-K (LTR5/5Hs), due to its expression in early embryogenesis [181–183], coding capacity of some members [30, 184] and potential roles for its proteins in cancer and other diseases [30–33, 185].”
BackgroundMammalian Endogenous Retroviruses
Mager, D. L., & Stoye, J. P. (2015) · Microbiology Spectrum · doi:10.1128/microbiolspec.mdna3-0009-2014 · Cited by 237 · see citing works
Bendall, M. L., Rougvie, M. D. M., Iñiguez, L., Lecanda, A., Pérez‐Losada, M., Ostrowski, M., Jones, R. B., Mulder, L. C. F., Reyes‐Terán, G., Crandall, K. A., et al. (2019) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006453 · Cited by 199 · see citing works
Panda, A., de Cubas, A. A., Stein, M., Riedlinger, G., Kra, J., Mayer, T., Smith, C. C., Vincent, B. G., Serody, J. S., Beckermann, K. E., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.121522 · Cited by 181 · see citing works
Human endogenous retrovirus-K (HML-2): a comprehensive review
Montojo, M. G., Doucet-O’Hare, T. T., Henderson, L. J., & Nath, A. (2018) · Critical Reviews in Microbiology · doi:10.1080/1040841x.2018.1501345 · Cited by 211 · see citing works
“Four mRNAs have been described as products of HML-2 transcription (Hohn et al. 2013) (Figure 1).”
BackgroundThe impact of transposable elements on mammalian development
Garcia-Perez, J. L., Widmann, T. J., & Adams, I. R. (2016) · Development · doi:10.1242/dev.132639 · Cited by 196 · see citing works
“However, recent reports have identified polymorphic HERVK insertions in humans (Wildschutte et al., 2016, reviewed in Hohn et al., 2013) suggesting recent mobilization activity and the possibility that some HERV-K copies might retain the capability to mobilize in present-day humans.”
BackgroundViruses as potential pathogenic agents in systemic lupus erythematosus
Nelson, P., Rylance, P., Roden, D., Trela, M., & Tugnet, N. (2014) · Lupus · doi:10.1177/0961203314531637 · Cited by 115 · see citing works
Lemaître, C., Tsang, J., Bireau, C., Heidmann, T., & Dewannieux, M. (2017) · PLoS Pathogens · doi:10.1371/journal.ppat.1006451 · Cited by 128 · see citing works
Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptorsPreprint
Dembny, P., Newman, A., Singh, M., Hinz, M., Szczepek, M., Krüger, C., Adalbert, R., Dzaye, O., Trimbuch, T., Wallach, T., et al. (2019) · bioRxiv · doi:10.1101/721241 · Cited by 104 · see citing works
“The multicopy HERV-K(HML-2) group comprises numerous human-specific proviruses that are transcriptionally active in the brain (8-10).”
BackgroundLi, M., Radvanyi, L. G., Yin, B., Rycaj, K., Li, J., Chivukula, R., Lin, K., Lu, Y., Shen, J., Chang, D. Z., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0001 · Cited by 126 · see citing works
Molecular functions of human endogenous retroviruses in health and disease
Suntsova, M., Garazha, A., Ivanova, A., Kaminsky, D., Zhavoronkov, A. A., & Buzdin, A. A. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1947-6 · Cited by 99 · see citing works
“The role of HERVs in cancer is most likely limited to retrovirus-driven gene expression and does not involve their insertional activity [22].”
Human Endogenous Retrovirus K (HML-2) in Health and Disease
Xue, B., Sechi, L. A., & Kelvin, D. J. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.01690 · Cited by 113 · see citing works
“The existence of an infectious HERV-K (HML-2) provirus with low prevalence in the current human population cannot be completely ruled out (Hohn et al., 2013).”
BackgroundWallace, T. A., Downey, R. F., Seufert, C. J., Schetter, A., Dorsey, T. H., Johnson, C. A., Goldman, R., Loffredo, C., Yan, P.-S., Sullivan, F., et al. (2014) · Carcinogenesis · doi:10.1093/carcin/bgu114 · Cited by 88
“However, it is known that retroviral reactivation is induced by both hormone exposure and stress signaling (13,29,30), and these signaling pathways could become more commonly activated in African-American men.”
BackgroundZhou, F., Krishnamurthy, J., Wei, Y., Li, M., Hunt, K., Johanning, G., Cooper, L., & Wang-Johanning, F. (2015) · Oncoimmunology · doi:10.1080/2162402x.2015.1047582 · Cited by 81 · see citing works
“These most recently acquired proviruses of the HERV-K family can express viral proteins and produce viral particles.(16,17) In previous studies we reported that expression of HERV-K env protein in malignant BC cells”
BackgroundLock, F. E., Rebollo, R., Miceli-Royer, K., Gagnier, L., Kuah, S., Babaian, A., Sistiaga-Poveda, M., Lai, C. B., Nemirovsky, O., Serrano, I., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1405507111 · Cited by 75 · see citing works
Human endogenous retroviruses role in cancer cell stemness
Matteucci, C., Balestrieri, E., Argaw-Denboba, A., & Vallebona, P. S. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.10.001 · Cited by 88 · see citing works
Human Endogenous Retrovirus K in Cancer: A Potential Biomarker and Immunotherapeutic Target
Curty, G., Marston, J. L., Rougvie, M. D. M., Leal, F. E., Nixon, D. F., & Soares, M. A. (2020) · Viruses · doi:10.3390/v12070726 · Cited by 85 · see citing works
“introductions show full-length or almost complete sequence genomes, which are composed of gag, pol and env genes flanked by LTR regions [2].”
BackgroundMethodInfluentialMaking a virtue of necessity: the pleiotropic role of human endogenous retroviruses in cancer
Kassiotis, G., & Stoye, J. P. (2017) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2016.0277 · Cited by 75 · see citing works
Bhardwaj, N., Montesion, M., Roy, F., & Coffin, J. M. (2015) · Viruses · doi:10.3390/v7030939 · Cited by 70 · see citing works
“The detection of doubly spliced transcripts for np9, rec and the non-coding transcript hel [20,58] is detailed for individual proviruses in Table S4.”
BackgroundEndogenous retroviruses in development and health
Wang, J., Lu, X., Zhang, W., & Liu, G. (2023) · Trends in Microbiology · doi:10.1016/j.tim.2023.09.006 · Cited by 69 · see citing works
Human endogenous retroviruses in development and disease
Mao, J., Zhang, Q., & Cong, Y. (2021) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2021.10.037 · Cited by 77 · see citing works
“It has been recognized that the reactivation of HERVs is related to the occurrence and development of human aging-related diseases [94,95].”
BackgroundBalestrieri, E., Pica, F., Matteucci, C., Zenobi, R., Sorrentino, R., Argaw-Denboba, A., Cipriani, C., Bucci, I., & Vallebona, P. S. (2015) · BioMed Research International · doi:10.1155/2015/164529 · Cited by 72 · see citing works
“There is a general agreement that the reactivation of HERV-K and HERV-W families is associated with human diseases that develop mostly in adulthood and/or senescence [11, 35, 40] and for which a parallel age-related alteration of DNA methylation is known [41–45].”
BackgroundWidespread expression of the ancient HERV-K (HML-2) provirus group in normal human tissues
Burn, A., Roy, F., Freeman, M., & Coffin, J. M. (2022) · PLoS Biology · doi:10.1371/journal.pbio.3001826 · Cited by 71 · see citing works
“Some cancer cells and cell lines express the HML-2 structural protein Gag and can form mature viral particles [22–24], and anti-Gag antibodies have been reported in individuals suffering from multiple malignancies such as breast cancer, melanoma, and teratocarcinoma [25,26].”
BackgroundHERV-K activation is strictly required to sustain CD133+ melanoma cells with stemness features
Argaw-Denboba, A., Balestrieri, E., Serafino, A., Cipriani, C., Bucci, I., Sorrentino, R., Sciamanna, I., Gambacurta, A., Sinibaldi‐Vallebona, P., & Matteucci, C. (2017) · Journal of experimental & clinical cancer research : CR · doi:10.1186/s13046-016-0485-x · Cited by 64 · see citing works
“Likewise, HERV-K has been associated with cellular transformation and carcinogenesis [16, 23, 25].”
Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences
Contreras-Galindo, R., Kaplan, M. H., Dube, D., Gonzalez-Hernandez, M. J., Chan, S., Meng, F., Dai, M., Omenn, G. S., Gitlin, S. D., & Markovitz, D. M. (2015) · Journal of Virology · doi:10.1128/jvi.00544-15 · Cited by 64 · see citing works
Schmitt, K., Heyne, K., Roemer, K., Meese, E. U., & Mayer, J. M. (2015) · Mobile DNA · doi:10.1186/s13100-015-0035-7 · Cited by 83 · see citing works
“Discussion Several lines of evidence suggest biological significance of HERV-K(HML-2)-encoded proteins Rec and Np9 in the development of tumor diseases, for instance, germ cell tumors and melanoma (for reviews, see [2,37]).”
BackgroundLessons Learned from Mouse Mammary Tumor Virus in Animal Models
Dudley, J. P., Golovkina, T. V., & Ross, S. R. (2016) · ILAR Journal · doi:10.1093/ilar/ilv044 · Cited by 64 · see citing works
“It has been estimated that endogenous retroviruses account for approximately 8% of the human genome (Hohn et al. 2013).”
BackgroundRegulation of stem cell function and neuronal differentiation by HERV-K via mTOR pathway
Wang, T., Medynets, M., Johnson, K. R., Doucet-O’Hare, T. T., Disanza, B., Li, W., Xu, Y., Bagnell, A. M., Tyagi, R., Sampson, K., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2002427117 · Cited by 74 · see citing works
Ma, W., Hong, Z., Liu, H., Chen, X., Ding, L., Liu, Z., Zhou, F., & Yuan, Y. (2016) · BioMed Research International · doi:10.1155/2016/8201642 · Cited by 63 · see citing works
“The HERV-K family are transcriptionally active in several human cancer tissues [8, 9].”
BackgroundHuman endogenous retroviruses in neurologic disease
Christensen, T. (2016) · Apmis · doi:10.1111/apm.12486 · Cited by 61 · see citing works
“toward microglia in normal brain, and to macrophages in early MS lesions (22, 59).”
BackgroundDai, L., Valle, L. D., Miley, W., Whitby, D., Ochoa, A. C., Flemington, E. K., & Qin, Z. (2018) · Oncogene · doi:10.1038/s41388-018-0282-4 · Cited by 66 · see citing works
Mameli, G., Erre, G., Caggiu, E., Mura, S., Cossu, D., Bo, M., Cadoni, M., Piras, A., Mundula, N., Colombo, E., et al. (2017) · Clinical and Experimental Immunology · doi:10.1111/cei.12964 · Cited by 56 · see citing works
Saito, T., Miyagawa, K., Chen, S.-Y., Tamošiūnienė, R., Wang, L., Sharpe, O., Samayoa, E., Harada, D., Moonen, J.-R. A. J., Cao, A., et al. (2017) · Circulation · doi:10.1161/circulationaha.117.027589 · Cited by 63 · see citing works
Do Human Endogenous Retroviruses Contribute to Multiple Sclerosis, and if So, How?
Morris, G., Maes, M. H. J., Murdjeva, M., & Puri, B. K. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1255-x · Cited by 57 · see citing works
Friends-Enemies: Endogenous Retroviruses Are Major Transcriptional Regulators of Human DNA
Buzdin, A., Prassolov, V., & Garazha, A. (2017) · Frontiers in Chemistry · doi:10.3389/fchem.2017.00035 · Cited by 52 · see citing works
“The role of HERVs in cancer is most likely limited to regulation of gene expression (Hohn et al., 2013).”
BackgroundMichaud, H., Rougvie, M. D. M., SenGupta, D., Deeks, S. G., Martin, J. N., Pilcher, C. D., Hecht, F. M., Sacha, J. B., & Nixon, D. F. (2014) · Retrovirology · doi:10.1186/1742-4690-11-10 · Cited by 54 · see citing works
“Although the only prior study that demonstrated TM protein expression was during pregnancy in the extravillous cytotrophoblast, TM seems to be absent from the cellular membrane at a normal physiological state [33,42].”
BackgroundResultHuman endogenous retrovirus HERV‐K(HML‐2) activity in prostate cancer is dominated by a few loci
Goering, W., Schmitt, K., Dostert, M., Schaal, H., Deenen, R., Mayer, J., & Schulz, W. (2015) · The Prostate · doi:10.1002/pros.23095 · Cited by 50
“HML-2 expression has been assessed in various human cancers (reviewed in [6,14]).”
BackgroundBendall, M., de Mulder, M., Iñiguez, L., Lecanda, A., Sánchez, Pérez-Losada, M., Ostrowski, M. A., Jones, R. B., Mulder, F., Reyes-Terán, G., et al. (2019) · Intrusive Beauty · doi:10.2307/j.ctv224tzgv.3 · Cited by 48
“Earlier studies have suggested that the HERV-K(HML-2) family (hereafter 3 referred to as HML-2) is expressed in human tissue and may be relevant to human health 4 (Hohn et al. 2013; Grow et al. 2015; Li et al. 2015; Weiss 2016).”
BackgroundHuman endogenous retroviruses in cancer: Expression, regulation and function (Review)
Gao, Y., Yu, X., & Chen, T. (2020) · Oncology Letters · doi:10.3892/ol.2020.12382 · Cited by 52 · see citing works
“mutations; however, there are still relatively intact open reading frames in a few HERV groups, such as HERV‐K HML‐2, which is the most active subtype of HERV‐K and will be abbreviated to HK2 hereafter (3).”
BackgroundHERV ‐K( HML ‐2), a seemingly silent subtenant – but still waters run deep
Hanke, K., Höhn, O., & Bannert, N. (2016) · Apmis · doi:10.1111/apm.12475 · Cited by 53 · see citing works
“[reviewed in (181)], there is no conclusive picture of whether complementation by HERV is likely to occur in vivo.”
BackgroundSelf-citationFrost, B., & Dubnau, J. (2024) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-082823-020615 · Cited by 45 · see citing works
Nexø, B. A., Villesen, P., Nissen, K. K., Lindegaard, H., Rossing, P. R., Petersen, T., Tarnow, L., Hansen, B. D., Lorenzen, T., Hørslev‐Petersen, K., et al. (2015) · Immunologic Research · doi:10.1007/s12026-015-8671-z · Cited by 53 · see citing works
“Interestingly, HERV-K13 also has an ORF for a 901 aa long Gag protein.”
BackgroundInfluentialHolloway, J. R., Williams, Z. H., Freeman, M. M., Bulow, U., & Coffin, J. M. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1814203116 · Cited by 40 · see citing works
“Human endogenous retroviruses (HERVs) constitute ∼8% of the genome (8), with ∼30 HERV groups represented (5, 9).”
BackgroundU6 snRNA Pseudogenes: Markers of Retrotransposition Dynamics in Mammals
Doucet, A. J., Droc, G., Siol, O., Audoux, J., & Gilbert, N. (2015) · Molecular Biology and Evolution · doi:10.1093/molbev/msv062 · Cited by 62 · see citing works
“Key words: retrotransposon, long interspersed nuclear element, small nuclear RNA.”
BackgroundStricker, E., Peckham‐Gregory, E. C., & Scheurer, M. E. (2023) · Biomedicines · doi:10.3390/biomedicines11030936 · Cited by 46 · see citing works
“Interestingly, the menstru- ation-associated hormones estradiol and progesterone were observed to increase HERV- K (HML-4) env [65] and HERV-K (HML-4) RT transcripts as well as HERV-K (HML-4) RT protein levels [66] in breast cancer cell lines (Figure 1).”
BackgroundInfluentialBaldwin, E. T., Götte, M., Tchesnokov, E. P., Arnold, E., Hagel, M., Nichols, C. E., Dossang, P., Lamers, M. B. A. C., Wan, P., Steinbacher, S., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2200260119 · Cited by 43 · see citing works
Durnaoglu, S., Lee, S.-K., & Ahnn, J. (2021) · Molecules and Cells · doi:10.14348/molcells.2021.5016 · Cited by 45 · see citing works
“The important topics have been extensively reviewed elsewhere (Garcia-Montojo et al., 2018; Hohn et al., 2013).”
BackgroundManghera, M., Ferguson, J., & Douville, R. (2015) · Viruses · doi:10.3390/v7010320 · Cited by 39
“) associated with several inflammatory and neurological diseases [1–7], few studies have sought to specifically examine ERVK polymerase (pol) gene and RT protein expression [8–11].”
BackgroundDi Giorgio, E., & Xodo, L. E. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.917998 · Cited by 39 · see citing works
“To sum up, ERVs were found to be reactivated and actively transcribed in patients with autoimmune diseases, neurodegeneration, cancer (139, 145, 146) and during physiological aging (123, 127, 131, 147).”
BackgroundAncient Adversary – HERV-K (HML-2) in Cancer
Dervan, E., Bhattacharyya, D. D., McAuliffe, J. D., Khan, F. H., & Glynn, S. A. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.658489 · Cited by 47 · see citing works
“-1 base pair (bp) ribosomal frameshifting at two slippery sites within the full-length mRNA allows for the production of Gag, Gag-Pro, and Gag-Pro-Pol fusion proteins (23).”
BackgroundThe role of endogenous retroviruses‐K in human cancer
Salavatiha, Z., Soleimani‐Jelodar, R., & Jalilvand, S. (2020) · Reviews in Medical Virology · doi:10.1002/rmv.2142 · Cited by 55 · see citing works
“lose a splice donor site and are unable to produce Rec; instead they encode NP9 protein (Figure 1).(16,17) Enhanced transcription of accessory proteins Rec and Np9 can be found in to various tumors.”
BackgroundLow HERV-K(C4) Copy Number Is Associated With Type 1 Diabetes
Mason, M., Speake, C., Gersuk, V., Nguyen, Q.-A., O'Brien, K., Odegard, J., Buckner, J., Greenbaum, C., Chaussabel, D., & Nepom, G. (2014) · Diabetes · doi:10.2337/db13-1382 · Cited by 37
“In addition to long terminal repeats, HERVs contain gag, pro, pol, and env genes and make up ;8–9% of the human genome (16).”
BackgroundMorandi, E., Tănăsescu, R., Tarlinton, R. E., Constantin‐Teodosiu, D., & Gran, B. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2018.03092 · Cited by 35 · see citing works
“Although there is no evidence that HERV-W can function as a retrovirus capable of retrotranscription, some HERVs, and in particular HERV-K, can (31).”
BackgroundAdvancements in Human Breast Cancer Targeted Therapy and Immunotherapy
Bou-Dargham, M. J., Draughon, S. A., Cantrell, V., Khamis, Z. I., & Sang, Q. A. (2021) · Journal of Cancer · doi:10.7150/jca.64205 · Cited by 37 · see citing works
Macfarlane, C. M., & Badge, R. M. (2015) · Retrovirology · doi:10.1186/s12977-015-0162-8 · Cited by 43 · see citing works
“Within the present-day census of HERV-K(HML-2) proviruses in the human population none have the capacity to autonomously produce infectious particles [70].”
BackgroundThe HERV-K Human Endogenous Retrovirus Envelope Protein Antagonizes Tetherin Antiviral Activity
Lemaître, C., Harper, F., Pierron, G., Heidmann, T., & Dewannieux, M. (2014) · Journal of Virology · doi:10.1128/jvi.02234-14 · Cited by 32 · see citing works
Ko, E.-J., Ock, M.-S., Choi, Y. H., Iovanna, J., Mun, S., Han, K., Kim, H., & Cha, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22083941 · Cited by 37 · see citing works
Aging-associated patterns in the expression of human endogenous retroviruses
Nevalainen, T., Autio, A., Mishra, B. H., Marttila, S., Jylhä, M. K., & Hurme, M. (2018) · PLoS ONE · doi:10.1371/journal.pone.0207407 · Cited by 37 · see citing works
Expression of the pol gene of human endogenous retroviruses HERV-K and -W in leukemia patients
Bergallo, M., Montanari, P., Mareschi, K., Merlino, C., Berger, M., Bini, I., Daprá, V., Galliano, I., & Fagioli, F. (2017) · Archives of Virology · doi:10.1007/s00705-017-3526-7 · Cited by 33
Glinsky, G. V. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.08.001 · Cited by 38 · see citing works
Singh, M., Cai, H., Bunse, M., Feschotte, C., & Izsvák, Z. (2020) · Viruses · doi:10.3390/v12111303 · Cited by 31 · see citing works
“For this, we investigated 216 the chromatin state at ~600 full-length LTR5_Hs sequences using the uniquely mappable reads in 9 217 different cell types from the ENCODE project [50].”
MethodResultAmarante, M. K., Pereira, N. D. S., Vitiello, G. A. F., & Watanabe, M. A. E. (2019) · Microbial Pathogenesis · doi:10.1016/j.micpath.2019.03.021 · Cited by 36 · see citing works
Glinsky, G. V. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.04.014 · Cited by 33 · see citing works
Garazha, A., Ivanova, A., Suntsova, M., Malakhova, G., Roumiantsev, S. A., Zhavoronkov, A., & Buzdin, A. (2015) · Cell Cycle · doi:10.1080/15384101.2015.1022696 · Cited by 31 · see citing works
“Genomics 2004; 84(3):596-9; PMID:15498467; http://dx.”
Interplay between endogenous and exogenous human retroviruses.
Kyriakou, E., & Magiorkinis, G. (2023) · Trends in Microbiology · doi:10.1016/j.tim.2023.03.008 · Cited by 30 · see citing works
Human Endogenous Retroviruses: Our Genomic Fossils and Companions
Stein, R. A., & DePaola, R. V. (2023) · Physiological Genomics · doi:10.1152/physiolgenomics.00171.2022 · Cited by 29 · see citing works
Weyerer, V., Strissel, P. L., Stöhr, C., Eckstein, M., Wach, S., Taubert, H. W., Brandl, L., Geppert, C. I., Wullich, B., Cynis, H., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.657187 · Cited by 29 · see citing works
“It is estimated for ERV-K HML1 through HML10 that ~600 proviruses and ~4,400 solo-LTRs exist (4, 5).”
BackgroundLi, W., Lin, L., Malhotra, R., Yang, L., Acharya, R. S., & Poss, M. L. (2019) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006564 · Cited by 37 · see citing works
Stearrett, N., Dawson, T., Rahnavard, A., Bachali, P., Bendall, M. L., Zeng, C., Caricchio, R., Pérez‐Losada, M., Grammer, A. C., Lipsky, P. E., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.661437 · Cited by 28 · see citing works
“However, it is increasingly clear from the analysis of RNA-Sequencing (RNA-Seq) data that functional HERVs, defined by the presence of 5’ and 3’ Long Terminal Repeat (LTR) regions with an open reading frame in between, remain in the human genome and their expression may have roles in a diversity of diseases (9, 10).”
BackgroundMustelin, T., & Ukadike, K. C. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.593891 · Cited by 55 · see citing works
“What we can conclude using computational tools from the ~120 genomic loci still present today is that HERV-K(HML-2) first entered our ancestral early hominin germline genome over 30 million years ago (28) and then continued to insert again and again into our germline genome until very recently in evolutionary time (29…”
MethodEndogenous Retroviruses and Human Cancer: Is There Anything to the Rumors?
Bhardwaj, N., & Coffin, J. M. (2014) · Cell Host & Microbe · doi:10.1016/j.chom.2014.02.013 · Cited by 22 · see citing works
“In melanoma, approximately 16%–22% of patients develop an antibody response against HML-2 Env and Gag proteins (Hohn et al., 2013).”
BackgroundInfluentialLiu, M., Jia, L., Li, H., Liu, Y., Han, J., Wang, X., Li, T., Li, J., Zhang, B., Zhai, X., et al. (2022) · Microbiology Spectrum · doi:10.1128/spectrum.00485-22 · Cited by 27 · see citing works
“5 kb in length and consists of four overlapping genes that encode structural and nonstructural proteins, with an LTR structure (59 LTR-gag-pro-pol-env-39 LTR) at each terminus (5, 12).”
BackgroundSantander, C., Gambron, P., Marchi, E., Karamitros, T., Katzourakis, A., & Magiorkinis, G. (2017) · Virus Evolution · doi:10.1093/ve/vex023 · Cited by 25 · see citing works
“The influence that TEs and human endogenous retroviruses (HERVs) have on altering genetic activity due to somatic rearrangements also implies a potential role in the development of disease (Hohn et al. 2013) for example through insertional mutagenesis (Djebali et al.”
BackgroundBalestrieri, E., Argaw-Denboba, A., Gambacurta, A., Cipriani, C., Bei, R., Serafino, A., Vallebona, P. S., & Matteucci, C. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.01448 · Cited by 24 · see citing works
“HERV-K DNA-polymorphisms, mRNA and proteins have been detected in cancer cells; in addition, viral particles have been identified in tissue, serum, and cell lines (Hohn et al., 2013).”
BackgroundXue, B., Zeng, T., Jia, L., Yang, D., Lin, S. L., Sechi, L., & Kelvin, D. (2020) · Retrovirology · doi:10.1186/s12977-020-00519-z · Cited by 22 · see citing works
Exploring HERV-K (HML-2) Influence in Cancer and Prospects for Therapeutic Interventions
Costa, B., & Vale, N. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914631 · Cited by 19 · see citing works
“The most recently integrated and best conserved human proviruses are found in the HERV-K family (HML-2) [10].”
BackgroundLatifi, T., Zebardast, A., & Marashi, S. M. (2021) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2021.103318 · Cited by 20 · see citing works
Human endogenous retroviruses and exogenous viral infections
Bao, C., Gao, Q., Xiang, H., Shen, Y., Chen, Q., Gao, Q., Cao, Y., Zhang, M., He, W., & Mao, L. (2024) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2024.1439292 · Cited by 20 · see citing works
Chignola, R., Sega, M., Molesini, B., Baruzzi, A., Stella, S., & Milotti, E. (2018) · bioRxiv · doi:10.1371/journal.pone.0206713 · Cited by 20
Curzio, D. L. D., Gurm, M., Turnbull, M., Nadeau, M.-J., Meek, B., Rempel, J. D., Fineblit, S., Jonasson, M. E., Hebert, S., Ferguson-Parry, J., et al. (2020) · Cells · doi:10.3390/cells9071584 · Cited by 21 · see citing works
“ERVK is the most recently endogenized retrovirus and most biologically active in humans, with approximately 1000 genomic ERVK insertions identified [27].”
Autio, A., Nevalainen, T., Mishra, B. H., Jylhä, M. K., Flinck, H., & Hurme, M. (2020) · Immunity & Ageing · doi:10.1186/s12979-020-00182-0 · Cited by 22 · see citing works
“The most recently integrated proviruses, belonging to the HERV-K (HML-2) family, are relatively well preserved and have retained considerable expression capacity [10].”
BackgroundDysregulated expression of repetitive DNA in ER+/HER2- breast cancer.
Yandım, C., & Karakülah, G. (2019) · Cancer Genetics · doi:10.1016/j.cancergen.2019.09.002 · Cited by 19 · see citing works
Retroviral envelope proteins: Involvement in neuropathogenesis
Hansen, D. T., Petersen, T., & Christensen, T. (2017) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2017.07.027 · Cited by 19 · see citing works
The Immune System and Responses to Cancer: Coordinated Evolution
Coventry, B. J., & Henneberg, M. (2021) · F1000Research · doi:10.12688/f1000research.6718.3 · Cited by 14 · see citing works
“…(HERVs) are estimated to make up 8% of the human genome, though fragmented and replication incompetent, it bears testament to long and intimate genetic interactions between a parasite with a few genes and 10,000 nucleotides, and a host of some 22,000 genes and some 2.85 billion nucleotides 10,11 .”
BackgroundInfluentialFowler, M., Theunissen, F., Carr, J. M., & Rogers, M. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03472-y · Cited by 23 · see citing works
“Human endogenous mouse mammary tumour virus like-2 (HML-2) is the best preserved HERV-K element, maintaining the capability of encoding viral proteins such as the env protein [164].”
BackgroundImplications of Endogenous Retroelements in the Etiopathogenesis of Systemic Lupus Erythematosus
Ukadike, K. C., & Mustelin, T. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10040856
“The modern human genome does not appear to contain any fully intact and functional HERVs anymore [59,61,62], but there still are about a dozen HERVs that encode for proteins that have some, or all, of their original functions [60-64].”
BackgroundHuman Endogenous Retrovirus Expression in Primary Cutaneous T-Cell Lymphomas
Fava, P., Bergallo, M., Astrua, C., Brizio, M., Galliano, I., Montanari, P., Tovo, P., Novelli, M., Savoia, P., Quaglino, P., et al. (2015) · Dermatology · doi:10.1159/000438669 · Cited by 18
Liu, H., Bergant, V., Frishman, G., Ruepp, A., Pichlmair, A., Vincendeau, M., & Frishman, D. (2022) · Viruses · doi:10.3390/v14071591 · Cited by 19 · see citing works
“Several HERV-K(HML-2) proviruses still encode the retroviral proteins gag, pol, and env [57].”
BackgroundWang, X., Hefton, A., Ni, K., Ukadike, K. C., Bowen, M. A., Eckert, M. M., Stevens, A. M., Lood, C., & Mustelin, T. (2021) · The Journal of Rheumatology · doi:10.3899/jrheum.201492 · Cited by 18 · see citing works
The WTX Tumor Suppressor Interacts with the Transcriptional Corepressor TRIM28*
Kim, W. J., Wittner, B., Amzallag, A., Brannigan, B. W., Ting, D., Ramaswamy, S., Maheswaran, S., & Haber, D. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.631945 · Cited by 17 · see citing works
“Similarly, re-expression of endogenous retroviral elements has been reported in several tumor types (32, 33), and satellite repeats are aberrantly expressed in BRCA1 mutant breast cancers (34, 35).”
BackgroundHuman Endogenous Retrovirus-K (HML-2)-Related Genetic Variation: Human Genome Diversity and Disease
Shin, W., Mun, S., & Han, K. (2023) · Genes · doi:10.3390/genes14122150 · Cited by 17 · see citing works
“The core gene pro encodes a deoxyuridine 5 (cid:48) -triphosphate nucleotide hydrolase (dUTPase) and a protease [32].”
BackgroundInfluentialSpecific human endogenous retroviruses predict metastatic potential in uveal melanoma
Bendall, M. L., Francis, J. H., Shoushtari, A. N., & Nixon, D. F. (2022) · JCI Insight · doi:10.1172/jci.insight.147172 · Cited by 15 · see citing works
“HERV expression is thought to be tightly controlled by intrinsic mechanisms, such as PIWI (33), APOBEC (34, 35), and other restricting mechanisms (36), which function to contain nucleic acids within a cell.”
Gray, L. R., Jackson, R., Jackson, P., Bekiranov, S., Rekosh, D. M., & Hammarskjöld, M. (2019) · Retrovirology · doi:10.1186/s12977-019-0505-y · Cited by 16 · see citing works
Sokol, M., Jessen, K. M., & Pedersen, F. (2015) · Retrovirology · doi:10.1186/s12977-015-0161-9 · Cited by 16 · see citing works
“Moreover, transcription of the HERV-K (HML2) consensus sequence results in the assembly of infectious particles that are inhibited by restriction factors including APOBEC family members [5,6].”
BackgroundNogueira, M. A. D. S., Gavioli, C. F. B., Pereira, N. Z., de Carvalho, G. C., Domingues, R., Aoki, V., & Sato, M. N. (2014) · Archives of Dermatological Research · doi:10.1007/s00403-014-1524-0 · Cited by 21 · see citing works
“Human chromosomes contain numerous HERV sequences that account up to 8 % of our genome [12].”
BackgroundCurty, G., Beckerle, G. A., Iñiguez, L., O’Brien, R. L. F., de Carvalho, P. S., Marston, J. L., Champiat, S., Heymann, J. J., Ormsby, C. E., Reyes‐Terán, G., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.553983 · Cited by 17 · see citing works
- Authors
- Hohn, O., Hanke, K., & Bannert, N.
- Affiliations
- Robert Koch Institute (DE)
- Corresponding author
- Bannert, Norbert
- ORCID
- Hanke, Kirsten
- Venue
- Frontiers in Oncology
- Publisher
- Frontiers Media SA
- Published
- 2013
- Volume
- 3
- Pages
- 246-246
- ISSN
- 2234-943X (ISSN-L)
- PMC
- PMC3778440
- OpenAlex
- W2134228703
- Cited by
- 196
- References
- 166
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 10 · 2023: 11 · 2022: 20 · 2021: 16 · 2020: 24 · 2019: 13 · 2018: 10 · 2017: 11 · 2016: 18 · 2015: 27 · 2014: 14
- FWCI
- 2.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Oncology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Publication server of the Robert Koch Institute (Robert Kock Institute) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- HERV-K(HML-2), human endogenous retroviruses, endogenization, host-virus coevolution, viral protein expression, carcinogenesis, retroviral infection
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