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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 May 15;90(10):4480–4484. doi: 10.1073/pnas.90.10.4480

Identification of human endogenous retroviruses with complex mRNA expression and particle formation.

R Löwer 1, K Boller 1, B Hasenmaier 1, C Korbmacher 1, N Müller-Lantzsch 1, J Löwer 1, R Kurth 1
PMCID: PMC46535  PMID: 8506289

Abstract

Retroviruses comprise strains with considerable disease potential in animals and humans. In addition to exogenous strains transmitted horizontally, endogenous proviruses are transmitted through the germ line. Some of these endogenous retroviruses can be pathogenic in mice and possibly in other animal species. They may also be considered as mobile genetic elements with the potential to produce mutations. In humans, genomic DNA contains numerous endogenous retroviral sequences detected by their partial relatedness to animal retroviruses. However, all proviruses sequenced so far have been found to be defective. In this communication, we describe the expression of a family of human endogenous retrovirus sequences (HERV-K) in GH cells, a teratocarcinoma cell line producing the human teratocarcinoma-derived retrovirus (HTDV) particles previously described by us. Four viral mRNA species could be identified, including a full-length mRNA. The other three subgenomic mRNAs are generated by single or double splicing events. This expression pattern is reminiscent of the more complex control of virus gene regulation observed, for example, with lenti- or spumavirus strains, although HERV-K shows no sequence homology to human T-lymphotropic virus or human immunodeficiency virus. Sequence analysis of expressed HERV-K genomes revealed non-defective gag genes, a prerequisite for particle formation. Open reading frames were also observed in pol and env. Antisera raised against recombinant gag proteins of HERV-K stained HTDV particles in immunoelectron microscopy, linking them to the HERV-K family.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baier M., Behr E., Kurth R., König H. Cloning and expression of the complete SIVagm pol region in E. coli. Purification and partial characterization of the reverse transcriptase. Arzneimittelforschung. 1990 Nov;40(11):1284–1287. [PubMed] [Google Scholar]
  2. Berger J., Aepinus C., Dobrovnik M., Fleckenstein B., Hauber J., Böhnlein E. Mutational analysis of functional domains in the HIV-1 Rev trans-regulatory protein. Virology. 1991 Aug;183(2):630–635. doi: 10.1016/0042-6822(91)90992-k. [DOI] [PubMed] [Google Scholar]
  3. Boller K., Frank H., Löwer J., Löwer R., Kurth R. Structural organization of unique retrovirus-like particles budding from human teratocarcinoma cell lines. J Gen Virol. 1983 Dec;64(Pt 12):2549–2559. doi: 10.1099/0022-1317-64-12-2549. [DOI] [PubMed] [Google Scholar]
  4. Bronson D. L., Fraley E. E., Fogh J., Kalter S. S. Induction of retrovirus particles in human testicular tumor (Tera-1) cell cultures: an electron microscopic study. J Natl Cancer Inst. 1979 Aug;63(2):337–339. [PubMed] [Google Scholar]
  5. Callahan R., Drohan W., Tronick S., Schlom J. Detection and cloning of human DNA sequences related to the mouse mammary tumor virus genome. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5503–5507. doi: 10.1073/pnas.79.18.5503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Calnan B. J., Tidor B., Biancalana S., Hudson D., Frankel A. D. Arginine-mediated RNA recognition: the arginine fork. Science. 1991 May 24;252(5009):1167–1171. doi: 10.1126/science.252.5009.1167. [DOI] [PubMed] [Google Scholar]
  7. Cohen M., Kato N., Larsson E. ERV3 human endogenous provirus mRNAs are expressed in normal and malignant tissues and cells, but not in choriocarcinoma tumor cells. J Cell Biochem. 1988 Feb;36(2):121–128. doi: 10.1002/jcb.240360203. [DOI] [PubMed] [Google Scholar]
  8. Deen K. C., Sweet R. W. Murine mammary tumor virus pol-related sequences in human DNA: characterization and sequence comparison with the complete murine mammary tumor virus pol gene. J Virol. 1986 Feb;57(2):422–432. doi: 10.1128/jvi.57.2.422-432.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gattoni-Celli S., Kirsch K., Kalled S., Isselbacher K. J. Expression of type C-related endogenous retroviral sequences in human colon tumors and colon cancer cell lines. Proc Natl Acad Sci U S A. 1986 Aug;83(16):6127–6131. doi: 10.1073/pnas.83.16.6127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kalter S. S., Helmke R. J., Heberling R. L., Panigel M., Fowler A. K., Strickland J. E., Hellman A. Brief communication: C-type particles in normal human placentas. J Natl Cancer Inst. 1973 Apr;50(4):1081–1084. doi: 10.1093/jnci/50.4.1081. [DOI] [PubMed] [Google Scholar]
  11. Kato N., Pfeifer-Ohlsson S., Kato M., Larsson E., Rydnert J., Ohlsson R., Cohen M. Tissue-specific expression of human provirus ERV3 mRNA in human placenta: two of the three ERV3 mRNAs contain human cellular sequences. J Virol. 1987 Jul;61(7):2182–2191. doi: 10.1128/jvi.61.7.2182-2191.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kato N., Shimotohno K., VanLeeuwen D., Cohen M. Human proviral mRNAs down regulated in choriocarcinoma encode a zinc finger protein related to Krüppel. Mol Cell Biol. 1990 Aug;10(8):4401–4405. doi: 10.1128/mcb.10.8.4401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Keydar I., Ohno T., Nayak R., Sweet R., Simoni F., Weiss F., Karby S., Mesa-Tejada R., Spiegelman S. Properties of retrovirus-like particles produced by a human breast carcinoma cell line: immunological relationship with mouse mammary tumor virus proteins. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4188–4192. doi: 10.1073/pnas.81.13.4188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. LUFT J. H. Improvements in epoxy resin embedding methods. J Biophys Biochem Cytol. 1961 Feb;9:409–414. doi: 10.1083/jcb.9.2.409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. La Mantia G., Maglione D., Pengue G., Di Cristofano A., Simeone A., Lanfrancone L., Lania L. Identification and characterization of novel human endogenous retroviral sequences prefentially expressed in undifferentiated embryonal carcinoma cells. Nucleic Acids Res. 1991 Apr 11;19(7):1513–1520. doi: 10.1093/nar/19.7.1513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lania L., Di Cristofano A., Strazzullo M., Pengue G., Majello B., La Mantia G. Structural and functional organization of the human endogenous retroviral ERV9 sequences. Virology. 1992 Nov;191(1):464–468. doi: 10.1016/0042-6822(92)90211-7. [DOI] [PubMed] [Google Scholar]
  17. Larsson E., Kato N., Cohen M. Human endogenous proviruses. Curr Top Microbiol Immunol. 1989;148:115–132. doi: 10.1007/978-3-642-74700-7_4. [DOI] [PubMed] [Google Scholar]
  18. Leib-Mösch C., Brack-Werner R., Werner T., Bachmann M., Faff O., Erfle V., Hehlmann R. Endogenous retroviral elements in human DNA. Cancer Res. 1990 Sep 1;50(17 Suppl):5636S–5642S. [PubMed] [Google Scholar]
  19. Löwer J., Wondrak E. M., Kurth R. Genome analysis and reverse transcriptase activity of human teratocarcinoma-derived retroviruses. J Gen Virol. 1987 Nov;68(Pt 11):2807–2815. doi: 10.1099/0022-1317-68-11-2807. [DOI] [PubMed] [Google Scholar]
  20. Löwer R., Löwer J., Frank H., Harzmann R., Kurth R. Human teratocarcinomas cultured in vitro produce unique retrovirus-like viruses. J Gen Virol. 1984 May;65(Pt 5):887–898. doi: 10.1099/0022-1317-65-5-887. [DOI] [PubMed] [Google Scholar]
  21. Löwer R., Löwer J., Tondera-Koch C., Kurth R. A general method for the identification of transcribed retrovirus sequences (R-U5 PCR) reveals the expression of the human endogenous retrovirus loci HERV-H and HERV-K in teratocarcinoma cells. Virology. 1993 Feb;192(2):501–511. doi: 10.1006/viro.1993.1066. [DOI] [PubMed] [Google Scholar]
  22. Malim M. H., Cullen B. R. HIV-1 structural gene expression requires the binding of multiple Rev monomers to the viral RRE: implications for HIV-1 latency. Cell. 1991 Apr 19;65(2):241–248. doi: 10.1016/0092-8674(91)90158-u. [DOI] [PubMed] [Google Scholar]
  23. Manns A., König H., Baier M., Kurth R., Grosse F. Fidelity of reverse transcriptase of the simian immunodeficiency virus from African green monkey. Nucleic Acids Res. 1991 Feb 11;19(3):533–537. doi: 10.1093/nar/19.3.533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Marrack P., Kushnir E., Kappler J. A maternally inherited superantigen encoded by a mammary tumour virus. Nature. 1991 Feb 7;349(6309):524–526. doi: 10.1038/349524a0. [DOI] [PubMed] [Google Scholar]
  25. May F. E., Westley B. R. Structure of a human retroviral sequence related to mouse mammary tumor virus. J Virol. 1986 Nov;60(2):743–749. doi: 10.1128/jvi.60.2.743-749.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mergia A., Shaw K. E., Pratt-Lowe E., Barry P. A., Luciw P. A. Identification of the simian foamy virus transcriptional transactivator gene (taf). J Virol. 1991 Jun;65(6):2903–2909. doi: 10.1128/jvi.65.6.2903-2909.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Moore R., Dixon M., Smith R., Peters G., Dickson C. Complete nucleotide sequence of a milk-transmitted mouse mammary tumor virus: two frameshift suppression events are required for translation of gag and pol. J Virol. 1987 Feb;61(2):480–490. doi: 10.1128/jvi.61.2.480-490.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mueller-Lantzsch N., Sauter M., Weiskircher A., Kramer K., Best B., Buck M., Grässer F. Human endogenous retroviral element K10 (HERV-K10) encodes a full-length gag homologous 73-kDa protein and a functional protease. AIDS Res Hum Retroviruses. 1993 Apr;9(4):343–350. doi: 10.1089/aid.1993.9.343. [DOI] [PubMed] [Google Scholar]
  29. Muranyi W., Flügel R. M. Analysis of splicing patterns of human spumaretrovirus by polymerase chain reaction reveals complex RNA structures. J Virol. 1991 Feb;65(2):727–735. doi: 10.1128/jvi.65.2.727-735.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ono M., Kawakami M., Ushikubo H. Stimulation of expression of the human endogenous retrovirus genome by female steroid hormones in human breast cancer cell line T47D. J Virol. 1987 Jun;61(6):2059–2062. doi: 10.1128/jvi.61.6.2059-2062.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Ono M. Molecular cloning and long terminal repeat sequences of human endogenous retrovirus genes related to types A and B retrovirus genes. J Virol. 1986 Jun;58(3):937–944. doi: 10.1128/jvi.58.3.937-944.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ono M., Yasunaga T., Miyata T., Ushikubo H. Nucleotide sequence of human endogenous retrovirus genome related to the mouse mammary tumor virus genome. J Virol. 1986 Nov;60(2):589–598. doi: 10.1128/jvi.60.2.589-598.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rabson A. B., Steele P. E., Garon C. F., Martin M. A. mRNA transcripts related to full-length endogenous retroviral DNA in human cells. Nature. 1983 Dec 8;306(5943):604–607. doi: 10.1038/306604a0. [DOI] [PubMed] [Google Scholar]
  34. Roberts J. D., Bebenek K., Kunkel T. A. The accuracy of reverse transcriptase from HIV-1. Science. 1988 Nov 25;242(4882):1171–1173. doi: 10.1126/science.2460925. [DOI] [PubMed] [Google Scholar]
  35. Schwartz S., Felber B. K., Benko D. M., Fenyö E. M., Pavlakis G. N. Cloning and functional analysis of multiply spliced mRNA species of human immunodeficiency virus type 1. J Virol. 1990 Jun;64(6):2519–2529. doi: 10.1128/jvi.64.6.2519-2529.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Seiki M., Hattori S., Hirayama Y., Yoshida M. Human adult T-cell leukemia virus: complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3618–3622. doi: 10.1073/pnas.80.12.3618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Siomi H., Shida H., Nam S. H., Nosaka T., Maki M., Hatanaka M. Sequence requirements for nucleolar localization of human T cell leukemia virus type I pX protein, which regulates viral RNA processing. Cell. 1988 Oct 21;55(2):197–209. doi: 10.1016/0092-8674(88)90043-8. [DOI] [PubMed] [Google Scholar]
  38. Skowronski J., Singer M. F. Expression of a cytoplasmic LINE-1 transcript is regulated in a human teratocarcinoma cell line. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6050–6054. doi: 10.1073/pnas.82.18.6050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tindall K. R., Kunkel T. A. Fidelity of DNA synthesis by the Thermus aquaticus DNA polymerase. Biochemistry. 1988 Aug 9;27(16):6008–6013. doi: 10.1021/bi00416a027. [DOI] [PubMed] [Google Scholar]
  40. Tokuyasu K. T., Dutton A. H., Geiger B., Singer S. J. Ultrastructure of chicken cardiac muscle as studied by double immunolabeling in electron microscopy. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7619–7623. doi: 10.1073/pnas.78.12.7619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tokuyasu K. T., Singer S. J. Improved procedures for immunoferritin labeling of ultrathin frozen sections. J Cell Biol. 1976 Dec;71(3):894–906. doi: 10.1083/jcb.71.3.894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Weeks K. M., Ampe C., Schultz S. C., Steitz T. A., Crothers D. M. Fragments of the HIV-1 Tat protein specifically bind TAR RNA. Science. 1990 Sep 14;249(4974):1281–1285. doi: 10.1126/science.2205002. [DOI] [PubMed] [Google Scholar]
  43. Wilkinson D. A., Freeman J. D., Goodchild N. L., Kelleher C. A., Mager D. L. Autonomous expression of RTVL-H endogenous retroviruslike elements in human cells. J Virol. 1990 May;64(5):2157–2167. doi: 10.1128/jvi.64.5.2157-2167.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wilkinson D. A., Freeman J. D., Goodchild N. L., Kelleher C. A., Mager D. L. Autonomous expression of RTVL-H endogenous retroviruslike elements in human cells. J Virol. 1990 May;64(5):2157–2167. doi: 10.1128/jvi.64.5.2157-2167.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. van Ooyen A. J., Michalides R. J., Nusse R. Structural analysis of a 1.7-kilobase mouse mammary tumor virus-specific RNA. J Virol. 1983 May;46(2):362–370. doi: 10.1128/jvi.46.2.362-370.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]

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