Hohenadl, Christine^*†; Leib-Mösch, Christine^*†; Hehlmann, Rüdiger^*; Erfle, Volker^*†

Summary: Endogenous retroviruses (ERVs) have been known for many years to exist in numerous natural and laboratory animal species. In humans it has been demonstrated that at least 1% of the genome consists of retrovirus-related sequences. Involvement of ERVs in the development of neoplastic and autoimmune diseases in the mouse model implicated a potentially pathogenic role of ERVs for humans, too. The research in this field led to a number of results strongly suggesting that human endogenous retroviral sequences (HERVs) are biologically active, on the RNA and even on the protein level. Particle formation, regulation or dysregulation of cellular gene expression, and synthesis of potentially pathogenic viral proteins indicate the broad spectrum of mechanisms by which HERVs may obtain biological significance.

Endogenous retroviruses (ERV) or retroviruslike genetic elements are the result of integration events of exogenous retroviruses into the DNA of germline cells. The fundamental structure of ERVs therefore resembles that of integrated exogenous retroviruses in the proviral form. Full-length ERVs contain sequences homologous to the gag, pol, and env genes of infectious retroviruses and are flanked by long terminal repeats (LTRs) containing the regulatory sequences that are necessary for retroviral transcription. Most ERVs discovered so far are inactivated by frameshifts or deletions and are replication defective. However, some full-length proviruses contain all the structural features that are essential for viral gene expression and replication. Therefore, ERVs represent a reservoir of possibly pathogenic viral genes that may be activated spontaneously or by environmental conditions.

A wide variety of endogenous and exogenous retroviruses has been detected in laboratory and wildgrown animals. Laboratory mice were an excellent model for primary studies, regarding the question of biological significance of ERVs, especially for diseases. Various mouse tissues were found to contain differentially expressed RNA or even proteins derived from ERVs (1). Endogenous murine leukemia viruses (MuLV) were activated by mutagens or ionizing radiation, leading to the formation of infectious particles (2). These viruses were found to be implicated in the induction of different neoplastic diseases such as leukemias, lymphomas, mammary carcinomas, and sarcomas (3-7). In addition to tumorigenesis, murine ERVs are considered to be involved in the development of several autoimmune diseases such as lupus, diabetes, and arthritis (reviewed in Ref. 8).

In the mouse system possible mechanisms of ERVs leading to carcinogenesis or autoimmune diseases have been elaborated. First, full-length ERVs can induce production of potentially pathogenic viral particles. In addition, replication-defective or partially deleted proviruses can encode for biologically active proteins. These proteins may influence cellular transcription, like some virally encoded transforming oncogenes (9), or interfere directly with the immune system. In this regard it has been shown that certain murine ERV-encoded envelope proteins appear to protect against retroviral infection (10,11). Others are known to possess immunosuppressive and antiinflammatory activity (12). Second, integration of proviruses near cellular promoters (13,14) may activate or enhance expression of cellular oncogenes and growth factor genes. Insertion of ERVs into cellular genes (reviewed in Ref. 15) can result in aberrant transcription or gene destruction (16,17).

The large numbers of endogenous retrovirus-related sequences in the human genome (reviewed in Refs. 18 and 19) combined with the intriguing data emerging from the mouse model allow speculation about the possible biological role of human endogenous retroviral sequences (HERVs). Transcription of HERVs was demonstrated in many different human tissues and cultured cells (reviewed in Refs. 19-21). However, no replication-competent HERV has been detected so far, and only a few HERVs are known to contain open reading frames. Nevertheless, the encoded proteins could be responsible for the development of different diseases comparable to the gene products of exogenous human retroviruses. This is further supported by demonstration of immunological reactivity against retroviral proteins in patients with autoimmune diseases and certain tumors of unknown etiology (reviewed in Refs. 19 and 22).

Autoimmune diseases are defined by the occurrence of autoantibodies reacting with self-epitopes. Expression of HERVs may lead to synthesis and immunologic presentation of retroviral proteins sharing amino acid sequence similarities with cellular proteins (molecular mimicry). There are several reports on ERV-encoded proteins that are supposed to induce autoimmunity by molecular mimicry of cellular proteins. For example, cross-reactivity with the p24 gag protein of human immunodeficiency virus type 1 (HIV-1) was demonstrated for sera of non-HIV-infected patients with primary Sjögren's syndrome (SS), a benign autoimmune disease characterized by lymphoid infiltration and final destruction of salivary and lacrimal glands (23). Antibodies to p24 gag of HIV-1 were also found in patients with systemic lupus erythematosus (SLE), an autoimmune disease closely related to SS. SLE is characterized mainly by autoantibodies to nuclear self-antigens, leading to the formation of pathogenic immune complexes. During the progression of SLE these complexes are deposited in the basement membranes of different organs, especially kidneys, resulting in severe malfunctions. In these patients, immunologic cross-reactivity between the p24 gag protein and the small ribonucleoprotein (snRNP) Sm was demonstrated (24). Since in both cases there was no evidence for HIV-1 infection, cross-reactivity to the p24 gag protein may be due to the presence of an endogenous retroviral protein sharing amino acid similarities. Another snRNP with a molecular weight of 70 kDa (U1 snRNP) was shown to contain an antigenic epitope with amino acid sequence similarity to the p30 gag protein of murine leukemia virus (MuLV) (25). This epitope exists in the core protein of most mammalian C-type retroviruses and probably is encoded also in the sequence of related endogenous elements that are present in the human genome in many copies. Another example for involvement of HERVs in autoimmune disease was given by Brookes et al. (26). Investigation of sera from patients with different autoimmune diseases (multiple sclerosis, SLE, SS) revealed the presence of antibodies reacting with synthetic peptides that represent the major epitopes of the human T-lymphotropic virus type I (HTLV-I) p19 gag protein and the homologous sequences of its endogenous counterpart HTLV-related endogenous sequence type 1 (HRES-1). HRES-1 expression in these patients was further detected in lymphoblastoid cells, salivary gland biopsies, and salivary gland epithelial cells in culture. This HRES was previously shown to be transcriptionally active in various human tissues and to contain two overlapping open reading frames (27). One of them is translated into a 28kDa protein that was localized in the cytoplasm and nuclear bodies of a human T-cell line (28).

Antigenic molecular mimicry, however, may not be the only way to induce autoimmunity. The human immune system may also be influenced or disturbed by so called superantigens encoded by endogenous retroviral sequences. Retroviruses such as mouse mammary tumor virus (MMTV) and its endogenous counterpart Mtv encode superantigens in the U3 regions of their LTRs (29,30). These superantigens are responsible for major histocompatibility complex (MHC) class II/antigen independent activation and depletion of certain classes of T lymphocytes (31). The subsequent release of cytokines by these activated T cells leads to a general and inappropriate response of the immune system, resulting in toxic shock and probably death. The human genome is known to contain several HERV families that are related to MMTV (32-35). Furthermore, there is some evidence for the existence of human endogenous superantigens (36,37) and recently MMTV superantigen-related sequences were detected in the human genome by polymerase chain reaction (PCR) using MMTV-specific oligonucleotide primers (38).

Besides exhibiting the potential for superantigen expression, one family of MMTV-related HERVs (HERV-K) was shown to be transcribed into mRNAs containing open reading frames for gag proteins and functional protease (39). The HERV-K family even comprises some full-length genomes altogether encoding the proteins required for retroviral replication. Synthesis of proteins encoded by the HERV-K env gene was demonstrated indirectly by the detection of antibodies against HERV-K outer membrane envelope proteins in human sera (40). Remarkably, especially high antibody levels against HERV-K10 gag proteins were found in patients with testicular tumors, in particular with seminomas. In these studies HERV-K10 gag protein synthesis was also detected in situ in seminoma tumor biopsies and in a teratocarcinoma-derived cell line (41). Correlation of HERV-K gag antibody titers with therapy indicated that these antibodies might have a diagnostic and prognostic value in seminoma tumor patients. However, the role of HERV-K10 in the development of this tumor is still unclear.

Although no replication-competent HERV has been detected so far, there are many reports demonstrating formation of particles with retroviral morphology. Such retrovirus-like particles have been demonstrated in lymphoblastoid cells exposed to mononuclear cells of a patient with severe CD4⁺ T-cell deficiency (42) and to homogenates of salivary tissue from patients with SS (43) or in normal human placentas (44). Furthermore, a human teratocarcinoma-derived cell line (GH) was found to produce retrovirus-like particles, the core proteins of which are most probably encoded by a HERV-K provirus (45,46). Increased expression of HERVs and particle production associated with reverse transcriptase activity was also observed in a hormone-stimulated human breast carcinoma-derived cell line (47). Analysis of these particles again revealed the endogenous origin of the packaged RNA. Since there was no complete uninterrupted open reading frame for all necessary proteins on a single transcript, these produced particles are probably generated by complementation of several HERVs.

Besides the synthesis of possibly pathogenic proteins there is a second way for endogenous retroviral sequences to influence cellular biology. Normally, ERVs are stable genetic elements, but in rare cases they may transpose, resulting in new integrations. Retroviral integration within a cellular gene may lead to its inactivation, whereas integration nearby a gene may alter its expression. Mutation of cellular genes as a result of retrotransposition has often been observed in nonprimate mammals (15). However, some recent cases of insertional mutagenesis caused by retrotransposable elements distantly related to HERVs were also detected in the human genome. For example, in a human breast cancer a somatically acquired integration of a LINE-1 element was found to disrupt the negative control elements of the c-myc protooncogene resulting in unregulated activation (48). Further de novo insertions of human LINE-1 elements have been identified by their deleterious effects on cellular genes in patients with colon cancer, hemophilia A, and Duchenne muscular dystrophy (reviewed in Ref. 49).

Insertion of retroviruses can modify the expression of neighboring cellular genes due to the transcriptional regulatory sequences contained in their LTRs. They may activate gene expression by providing promoter and/or enhancer sequences, influence tissue specificity, or provoke transcription termination. Several studies have demonstrated all of these effects. Concerning transcriptional activation, a solitary LTR of the ERV9 family was found to drive the expression of a gene potentially coding for a zinc-finger transcription factor (50). Similarly, ERV3 RNA transcripts were shown to contain genomic sequences at their 3' end encoding a Krüppel-related zinc-finger protein (51). Another chimeric transcript consisting of endogenous retroviral and nonretroviral RNA was detected in a human teratocarcinoma cell line. The nonretroviral part of this mRNA was shown to contain an open reading frame coding for a protein with homologies to distinct domains of phospholipase A2 and therefore designated PLA2L. The PLA2L gene is initiated in the 5' LTR of an HERV-H element and expressed as a spliced read-through transcript (52). In addition to initiation, examples were described where HERV LTRs provided polyadenylation signals for cellular transcripts (53-55). Altered tissue-specific gene expression due to the influence of a retroviral LTR was demonstrated for the human amylase gene complex. Samuelson et al. (56) identified a retroviral element of the HERV-E family that is inversely inserted within the 5' flanking region of three amylase genes. These three genes are specifically expressed in the salivary gland, whereas amylase genes lacking the retroviral element are specifically expressed in the pancreas. The amylase genes containing the intact retrovirus are transcribed from a second promoter near the retroviral LTR, which is activated by sequences derived from the 5' LTR of the inserted retroviral element (57). A high number of HERVs or solitary HERV LTRs is found in the vicinity of genes that code for histocompatibility and lymphocyte differentiation antigens. Several HERV-K elements have been found to be associated with the HLA-DQ locus (58) and the C2 complement gene (59). The retroviral LTRs are thought to be involved in gene rearrangements during cell differentiation and to influence expression of these immune regulatory genes, thereby leading to altered antigen presentation and, in consequence, to autoreactivity.

The various data presented above indicate that ERVs are biologically active not only in mice but also in humans. Although most HERVs discovered so far are incomplete and replication defective, there are at least some that are capable of forming particles. Most interesting are studies demonstrating the influence of endogenous retroviral elements on cellular gene expression. Insertional mutagenesis as well as transcriptional control by endogenous viral LTRs may have severe effects on regulation of cell biology. In different cases such events could already be associated with cellular malfunctions or altered tissue-specific expression. However, in most examples the consequences of HERV activities are still unclear and require further investigation. A lot of data are available on the presence of HERV-encoded proteins and antibodies directed against them in autoimmune diseases of yet unknown etiology. The still unresolved problem, however, is their specific relationship to disease. Therefore, much more work will be needed to elucidate the exact biological role of ERVs.

1. Stoye JP, Coffin JM. Endogenous viruses. In: Weiss R, Teich N, Varmus H, Coffin J, eds. RNA tumor viruses. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 1985:Vol. 2(Suppl.):357-404. [Context Link]

2. Janowski M, Cox R, Strauss PG. The molecular biology of radiation-induced carcinogenesis: thymic lymphoma, myeloid leukemia and osteosarcoma. Int J Rad Biol 1990;57:677-91. [Context Link]

3. Stoye JP, Coffin JM. The four classes of endogenous murine leukemia virus: structural relationships and potential for recombination. J Virol 1987;61:2659-69. ExternalResolverBasic Bibliographic Links [Context Link]

4. Etkind PR. Expression of the int-1 and int-2 loci in endogenous mouse mammary tumor virus-induced mammary tumorigenesis in the C3Hf mouse. J Virol 1989;63:4972-5. ExternalResolverBasic Bibliographic Links [Context Link]

5. Pedersen L, Strauss PG, Schmidt J, et al. Pathogenicity of BALB/c-derived N-tropic murine leukemia viruses. Virology 1990;179:931-5. ExternalResolverBasic Bibliographic Links [Context Link]

6. Speth C, Luz A, Strauss PG, et al. Akv murine leukemia virus enhances lymphomagenesis in myc-kappa transgenic and in wild-type mice. Virology 1995;206:93-9. ExternalResolverBasic Bibliographic Links [Context Link]

7. Schmidt J, Krump-Konvalinkova V, Luz A, et al. Akv murine leukemia virus enhances bone tumorigenesis in hMT-c-fos-LTR transgenic mice. Virology 1995;206:85-92. ExternalResolverBasic Bibliographic Links [Context Link]

8. Garry RF, Krieg AM, Cheevers WP, et al. Retroviruses and their roles in chronic inflammatory diseases and autoimmunity. In: Levy JA, ed. The Retroviridae. New York: Plenum Press, 1995:491-603. [Context Link]

9. Finkel MP, Reilly CA, Biskis BO. Viral etiology of bone cancer. Front Rad Ther Oncol 1975;10:28-39. [Context Link]

10. Buller RS, Van Zant G, Eldridge PW, Portis JL. A population of murine hematopoietic progenitors expresses an endogenous retroviral gp 70 linked to the Rmcf gene and associated with resistance to erythroleukemia. J Exp Med 1989;169:865-80. ExternalResolverBasic Bibliographic Links [Context Link]

11. Gardner MB, Kozak CA, O'Brien SJ. The Lake Casitas wild mouse: evolving genetic resistance to retroviral disease. Trends Genet 1991;7:22-7. ExternalResolverBasic Bibliographic Links [Context Link]

12. Snyderman R, Cianciolo GJ. Immunosuppressive activity of the retroviral envelope protein p15E and its possible relationship to neoplasia. Immunol Today 1984;5:240-4. ExternalResolverBasic Bibliographic Links [Context Link]

13. Horowitz M, Luria S, Rechavi G, Givol D. Mechanism of activation of the mouse c-mos oncogene by the LTR of an intracisternal A-particle gene. EMBO J 1984;3:2937-41. ExternalResolverBasic Bibliographic Links [Context Link]

14. Dührsen U, Stahl J, Gough NM. In vivo transformation of factor-dependent hematopoietic cells: role of intracisternal A-particle transposition for growth factor gene activation. EMBO J 1990;4:1087-96. [Context Link]

15. Favor J, Morawetz C. Insertional mutations in mammals and mammalian cells. Mutat Res 1992;284:53-74. ExternalResolverBasic Bibliographic Links [Context Link]

16. Adachi M, Watanabe-Fukunaga R, Nagata S. Aberrant transcription caused by the insertion of an early transposable element in an intron of the Fas antigen gene of lpr mice. Proc Natl Acad Sci USA 1993;90:1756-60. ExternalResolverBasic Bibliographic Links [Context Link]

17. Mitreiter K, Schmidt J, Luz A, et al. Disruption of the murine p53 gene by insertion of an endogenous retrovirus like element (ETn) in a cell line from radiation-induced osteosarcoma. Virology 1994;200:837-41. ExternalResolverBasic Bibliographic Links [Context Link]

18. Leib-Mösch C, Brack-Werner R, Werner T, et al. Endogenous retroviral elements in human DNA. Cancer Res 1990;50:5636s-42s. ExternalResolverBasic Bibliographic Links [Context Link]

19. Wilkinson DA, Mager DL, Leong JA. Endogenous human retroviruses. In: Levy J, ed. The Retroviridae. New York: Plenum Press, 1994:465-535. [Context Link]

20. Leib-Mösch C, Bachmann M, Brack-Werner R, Werner T, Erfle V, Hehlmann R. Expression and biological significance of human endogenous retroviral sequences. Leukemia 1992;6:72s-5s. ExternalResolverBasic Bibliographic Links [Context Link]

21. Perl A, Banki K. Human endogenous retroviral elements and autoimmunity: data and concepts. Trends Microbiol 1993;1:153-6. ExternalResolverBasic Bibliographic Links [Context Link]

22. Krieg AM, Gourley MF, Perl A. Endogenous retroviruses: potential etiologic agents in autoimmunity. FASEB J 1992;6:2537-44. [Context Link]

23. Talal N, Dauphinee MJ, Dany M, Alexander SS, Hart DJ, Garry RF. Detection of serum antibodies to retroviral proteins in patients with primary Sjögren's syndrome (autoimmune exocrinopathy). Arth Rheum 1990;33:774-81. ExternalResolverBasic Bibliographic Links [Context Link]

24. Talal N, Garry RF, Schur PH, et al. A conserved idiotype and antibodies to retroviral proteins in systemic lupus erythematosus. J Clin Invest 1990;85:1866-71. ExternalResolverBasic Bibliographic Links [Context Link]

25. Query CC, Keene JD. A human autoimmune protein associated with U1 A contains a region of homology that is cross-reactive with retroviral p30 gag antigen. Cell 1987;51:211-20. [Context Link]

26. Brookes SM, Pandolfino YA, Mitchell TJ, et al. The immune response to and expression of cross-reactive retroviral Gag sequences in autoimmune disease. Br J Rheumatol 1992;31:735-42. ExternalResolverBasic Bibliographic Links [Context Link]

27. Perl A, Rosenblatt J, Chen I, et al. Detection and cloning of new HTLV-related endogenous sequences in man. Nucleic Acids Res 1989;17:6841-54. ExternalResolverBasic Bibliographic Links [Context Link]

28. Banki K, Maceda J, Hurley E, et al. Human T-cell lymphotrophic virus (HTLV)-related endogenous sequence, HRES-1, encodes a 28 kDa protein: a possible autoantigen for HTLV-1 gag reactive autoantibodies. Proc Natl Acad Sci USA 1992;89:1939-43. ExternalResolverBasic Bibliographic Links [Context Link]

29. Choi Y, Kappler JW, Marrack P. A superantigen encoded in the open reading frame of the 3' long terminal repeat of mouse mammary tumour virus. Nature 1991;350:203-7. ExternalResolverBasic Bibliographic Links [Context Link]

30. Günzburg WH, Heinemann F, Wintersperger S, et al. Endogenous superantigen expression controlled by a novel promoter in the MMTV long terminal repeat. Nature 1993;364:154-8. ExternalResolverBasic Bibliographic Links [Context Link]

31. Acha-Orbea H, Palmer E. Mls-a retrovirus exploits the immune system. Immunol Today 1991;12:356-61. ExternalResolverBasic Bibliographic Links [Context Link]

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;589-98. [Context Link]

33. Deen KC, Sweet RW. 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;57:422-32. ExternalResolverBasic Bibliographic Links [Context Link]

34. Medstrand P, Blomberg J. Characterization of novel reverse transcriptase encoding human endogenous retroviral sequences similar to type A and type B retroviruses: differential transcription in normal human tissue. J Virol 1993;67:6778-87. [Context Link]

35. Leib-Mösch C, Haltmeier M, Werner T, et al. Genomic distribution and transcription of solitary HERV-LTRs. Genomics 1993;18:261-9. ExternalResolverBasic Bibliographic Links [Context Link]

36. Baccala R, Kone DH, Walker S, Balderas RS, Theofilopoulos AN. Genomically imposed and somatically modified human thymocyte V[beta] gene repertoires. Proc Natl Acad Sci USA 1991;88:2908-12. ExternalResolverBasic Bibliographic Links [Context Link]

37. Paliard X, West SG, Lafferty JA, et al. Evidence for the effects of a superantigen in rheumatoid arthritis. Science 1991;253:325-9. ExternalResolverBasic Bibliographic Links [Context Link]

38. Indraccolo S, Günzburg WH, Leib-Mösch C, Erfle V, Salmons B. Identification of three human sequences with viral superantigen-specific primers. Mammal Genome 1995;6:339-44. [Context Link]

39. Mueller-Lantzsch N, Sauter M, Weiskircher A, et al. 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;9:343-50. ExternalResolverBasic Bibliographic Links [Context Link]

40. Vogetseder W, Dumfahrt A, Mayersbach P, Schönitzer D, Dierich MP. Antibodies in human sera recognizing a recombinant outer membrane protein encoded by the envelope gene of the human endogenous retrovirus K. AIDS Res Hum Retroviruses 1993;9:687-94. ExternalResolverBasic Bibliographic Links [Context Link]

41. Sauter M, Schommer S, Kremmer E, et al. Human endogenous retrovirus K10: expression of gag protein and detection of antibodies in proteins with seminomas. J Virol 1995;69:414-21. ExternalResolverBasic Bibliographic Links [Context Link]

42. Gupta S, Ribak CE, Gollapudi S, Kim CH, Salahuddin SZ. Detection of a human intracisternal retroviral particle associated with CD4+ T-cell deficiency. Proc Natl Acad Sci USA 1992;89:7831-5. [Context Link]

43. Garry RF, Fermin CD, Darenn JH, Alexander SS, Donehower LA, Luo-Zhang H. Detection of a human intracisternal particle antigenetically related to HIV. Science 1990;250:1127-9. [Context Link]

44. Boller K, König H, Sauter M, et al. Evidence that HERV-K is the endogenous retrovirus sequence that encodes for the human teratocarcinoma-derived retrovirus HTDV. Virology 1993;196:349-53. ExternalResolverBasic Bibliographic Links [Context Link]

45. Lyden TW, Johnson PM, Mwenda JM, Rote NS. Ultrastructural characterization of endogenous retroviral particles isolated from normal human placentas. Biol Reprod 1994;51:152-7. ExternalResolverBasic Bibliographic Links [Context Link]

46. Löwer R, Boller K, Hasenmaier B, et al. Identification of human endogenous retroviruses with complex mRNA expression and particle formation. Proc Natl Acad Sci USA 1993;90:4480-4. [Context Link]

47. Seifarth W, Skladny H, Krieg-Schneider F, Reichert A, Hehlmann R, Leib-Mösch C. Retrovirus-like particles released from the human breast cancer cell line T47-D display type B- and C-related endogenous retroviral sequences. J Virol 1995;69:6408-16. ExternalResolverBasic Bibliographic Links [Context Link]

48. Morse B, Rotherg P, South V, Spandorfer J, Astrin S. Insertional mutagenesis of the myc locus by a LINE-1 sequence in a human breast carcinoma. Nature 1988;333:87-90. [Context Link]

49. Leib-Mösch C, Seifarth W. Evolution and biological significance of human retroelements. Virus Genes 1996;11 (in press). [Context Link]

50. Di Christofano A, Strazzullo M, Longo L, La Mantia G. Characterization and genomic mapping of the ZNF80 locus: expression of this zinc-finger gene is driven by a solitary LTR of ERV9 endogenous retroviral family. Nucleic Acids Res 1995;23:2823-30. ExternalResolverBasic Bibliographic Links [Context Link]

51. Kato N, Shimotohno K, Van Leeuwen D, Cohen M. Human proviral mRNAs down regulated in choriocarcinoma encode a zinc-finger protein related to Krüppel. Mol Cell Biol 1990;10:4401-5. ExternalResolverBasic Bibliographic Links [Context Link]

52. Feuchter-Murthy A, Freeman JD, Mager DL. Splicing of a human endogenous retrovirus to a novel phospholipase A2 related gene. Nucleic Acids Res 1993;21:135-43. [Context Link]

53. Tomita N, Horii A, Doi S, et al. Transcription of human endogenous retroviral long terminal repeat (LTR) sequence in a lung cancer cell line. Biochem Biophys Res Commun 1990;1:1-10. ExternalResolverBasic Bibliographic Links [Context Link]

54. Goodchild NL, Wilkinson DA, Mager DL. A human endogenous long terminal repeat provides a polyadenylation signal to a novel, alternatively spliced transcript in normal placenta. Gene 1992;121:287-94. ExternalResolverBasic Bibliographic Links [Context Link]

55. Leib-Mösch C, Bachmann M, Geigl EM, et al. Expression of S71-related sequences in human cells. In: Neth R, ed. Haematology and blood transfusion, Vol. 35. Modern trends in human leukemia IX. Berlin/Heidelberg: Springer Verlag, 1992:256-9. [Context Link]

56. Samuelson LC, Wiebauer K, Now CM, Meister MH. Retroviral and pseudogene insertion sites reveal the lineage of human salivary and pancreatic amylase genes from a single gene during primate evolution. Mol Cell Biol 1990;10:2513-20. ExternalResolverBasic Bibliographic Links [Context Link]

57. Ting CN, Rosenberg MP, Snow CM, Samuelson LC, Meisler MH. Endogenous retroviral sequences are required for tissue-specific expression of a human salivary amylase gene. Genes Dev 1992;6:1457-65. [Context Link]

58. Kambhu S, Falldorf P, Lee J. Endogenous retroviral long terminal repeats within the HLA-DQ locus. Proc Natl Acad Sci USA 1990;87:4927-31. ExternalResolverBasic Bibliographic Links [Context Link]

59. Zhu Z, Hsieh SL, Bentley D, Campbell R, Volanakis J. A variable number of tandem repeats locus within the human complement C2 gene is associated with a retroposon derived from a human endogenous retrovirus. J Exp Med 1992;175:1783-7. ExternalResolverBasic Bibliographic Links [Context Link]

Key Words: Endogenous retroviral sequences; Retrotransposition; Biological activity of endogenous retroviruses; Insertional mutagenesis

Proceedings of the VIIth International Conference on Human Retrovirology: HTLV