Abstract
Direct RNA-PCR analyses of T-cell lymphomas that developed in rhesus macaques during a gene transfer experiment revealed the presence of several different recombinant murine leukemia viruses (MuLV). Most prominent was the expected MuLV recombinant, designated MoLTRAmphoenv in which the amphotropic env of the helper packaging virus was joined to the long terminal repeat (LTR) of the Moloney MuLV-derived vector. This retrovirus does not exist in nature. An additional copy of the core enhancer acquired from the vector LTR may have augmented the replicative properties of MoLTRAmphoenv MuLV in several different rhesus cell types compared with the prototype amphotropic MuLV4070A. Unexpectedly, at least two types of mink cell focus-forming MuLV elements, arising from endogenous retroviral sequences expressed in the murine packaging cell line, were also transmitted and highly expressed in one of the macaques. Furthermore, murine virus-like VL-30 sequences were detected in the rhesus lymphomas, but these were not transcribed into RNA. The unanticipated presence of an array of MuLV-related structures in a primate gene transfer recipient demands ever-vigilant scrutiny for the existence of transmissible retroviral elements and replication-competent viruses possessing altered tropic or growth properties in packaging cells producing retroviral vectors.
Full Text
The Full Text of this article is available as a PDF (648.0 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Adachi A., Sakai K., Kitamura N., Nakanishi S., Niwa O., Matsuyama M., Ishimoto A. Characterization of the env gene and long terminal repeat of molecularly cloned Friend mink cell focus-inducing virus DNA. J Virol. 1984 Jun;50(3):813–821. doi: 10.1128/jvi.50.3.813-821.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Adams S. E., Rathjen P. D., Stanway C. A., Fulton S. M., Malim M. H., Wilson W., Ogden J., King L., Kingsman S. M., Kingsman A. J. Complete nucleotide sequence of a mouse VL30 retro-element. Mol Cell Biol. 1988 Aug;8(8):2989–2998. doi: 10.1128/mcb.8.8.2989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Amanuma H., Laigret F., Nishi M., Ikawa Y., Khan A. S. Identification of putative endogenous proviral templates for progenitor mink cell focus-forming (MCF) MuLV-related RNAs. Virology. 1988 Jun;164(2):556–561. doi: 10.1016/0042-6822(88)90573-9. [DOI] [PubMed] [Google Scholar]
- Anderson W. F., McGarrity G. J., Moen R. C. Report to the NIH Recombinant DNA Advisory Committee on murine replication-competent retrovirus (RCR) assays (February 17, 1993). Hum Gene Ther. 1993 Jun;4(3):311–321. doi: 10.1089/hum.1993.4.3-311. [DOI] [PubMed] [Google Scholar]
- Armentano D., Yu S. F., Kantoff P. W., von Ruden T., Anderson W. F., Gilboa E. Effect of internal viral sequences on the utility of retroviral vectors. J Virol. 1987 May;61(5):1647–1650. doi: 10.1128/jvi.61.5.1647-1650.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Battini J. L., Danos O., Heard J. M. Receptor-binding domain of murine leukemia virus envelope glycoproteins. J Virol. 1995 Feb;69(2):713–719. doi: 10.1128/jvi.69.2.713-719.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Battini J. L., Heard J. M., Danos O. Receptor choice determinants in the envelope glycoproteins of amphotropic, xenotropic, and polytropic murine leukemia viruses. J Virol. 1992 Mar;66(3):1468–1475. doi: 10.1128/jvi.66.3.1468-1475.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Belli B., Patel A., Fan H. Recombinant mink cell focus-inducing virus and long terminal repeat alterations accompany the increased leukemogenicity of the Mo+PyF101 variant of Moloney murine leukemia virus after intraperitoneal inoculation. J Virol. 1995 Feb;69(2):1037–1043. doi: 10.1128/jvi.69.2.1037-1043.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Besmer P., Olshevsky U., Baltimore D., Dolberg D., Fan H. Virus-like 30S RNA in mouse cells. J Virol. 1979 Mar;29(3):1168–1176. doi: 10.1128/jvi.29.3.1168-1176.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bestwick R. K., Kozak S. L., Kabat D. Overcoming interference to retroviral superinfection results in amplified expression and transmission of cloned genes. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5404–5408. doi: 10.1073/pnas.85.15.5404. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bodine D. M., McDonagh K. T., Brandt S. J., Ney P. A., Agricola B., Byrne E., Nienhuis A. W. Development of a high-titer retrovirus producer cell line capable of gene transfer into rhesus monkey hematopoietic stem cells. Proc Natl Acad Sci U S A. 1990 May;87(10):3738–3742. doi: 10.1073/pnas.87.10.3738. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brightman B. K., Farmer C., Fan H. Escape from in vivo restriction of Moloney mink cell focus-inducing viruses driven by the Mo+PyF101 long terminal repeat (LTR) by LTR alterations. J Virol. 1993 Dec;67(12):7140–7148. doi: 10.1128/jvi.67.12.7140-7148.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cloyd M. W., Hartley J. W., Rowe W. P. Lymphomagenicity of recombinant mink cell focus-inducing murine leukemia viruses. J Exp Med. 1980 Mar 1;151(3):542–552. doi: 10.1084/jem.151.3.542. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cornetta K., Moen R. C., Culver K., Morgan R. A., McLachlin J. R., Sturm S., Selegue J., London W., Blaese R. M., Anderson W. F. Amphotropic murine leukemia retrovirus is not an acute pathogen for primates. Hum Gene Ther. 1990 Spring;1(1):15–30. doi: 10.1089/hum.1990.1.1-15. [DOI] [PubMed] [Google Scholar]
- Cornetta K., Morgan R. A., Anderson W. F. Safety issues related to retroviral-mediated gene transfer in humans. Hum Gene Ther. 1991 Spring;2(1):5–14. doi: 10.1089/hum.1991.2.1-5. [DOI] [PubMed] [Google Scholar]
- Cornetta K., Morgan R. A., Gillio A., Sturm S., Baltrucki L., O'Reilly R., Anderson W. F. No retroviremia or pathology in long-term follow-up of monkeys exposed to a murine amphotropic retrovirus. Hum Gene Ther. 1991 Fall;2(3):215–219. doi: 10.1089/hum.1991.2.3-215. [DOI] [PubMed] [Google Scholar]
- Daniel M. D., Letvin N. L., King N. W., Kannagi M., Sehgal P. K., Hunt R. D., Kanki P. J., Essex M., Desrosiers R. C. Isolation of T-cell tropic HTLV-III-like retrovirus from macaques. Science. 1985 Jun 7;228(4704):1201–1204. doi: 10.1126/science.3159089. [DOI] [PubMed] [Google Scholar]
- Danos O., Mulligan R. C. Safe and efficient generation of recombinant retroviruses with amphotropic and ecotropic host ranges. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6460–6464. doi: 10.1073/pnas.85.17.6460. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Donahue R. E., Kessler S. W., Bodine D., McDonagh K., Dunbar C., Goodman S., Agricola B., Byrne E., Raffeld M., Moen R. Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer. J Exp Med. 1992 Oct 1;176(4):1125–1135. doi: 10.1084/jem.176.4.1125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fine D., Schochetman G. Type D primate retroviruses: a review. Cancer Res. 1978 Oct;38(10):3123–3139. [PubMed] [Google Scholar]
- Fynan E. F., Webster R. G., Fuller D. H., Haynes J. R., Santoro J. C., Robinson H. L. DNA vaccines: protective immunizations by parenteral, mucosal, and gene-gun inoculations. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11478–11482. doi: 10.1073/pnas.90.24.11478. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hartley J. W., Rowe W. P. Naturally occurring murine leukemia viruses in wild mice: characterization of a new "amphotropic" class. J Virol. 1976 Jul;19(1):19–25. doi: 10.1128/jvi.19.1.19-25.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hartley J. W., Wolford N. K., Old L. J., Rowe W. P. A new class of murine leukemia virus associated with development of spontaneous lymphomas. Proc Natl Acad Sci U S A. 1977 Feb;74(2):789–792. doi: 10.1073/pnas.74.2.789. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Herr W., Clarke J. The SV40 enhancer is composed of multiple functional elements that can compensate for one another. Cell. 1986 May 9;45(3):461–470. doi: 10.1016/0092-8674(86)90332-6. [DOI] [PubMed] [Google Scholar]
- Herr W., Gluzman Y. Duplications of a mutated simian virus 40 enhancer restore its activity. Nature. 1985 Feb 21;313(6004):711–714. doi: 10.1038/313711a0. [DOI] [PubMed] [Google Scholar]
- Higgins D. G., Bleasby A. J., Fuchs R. CLUSTAL V: improved software for multiple sequence alignment. Comput Appl Biosci. 1992 Apr;8(2):189–191. doi: 10.1093/bioinformatics/8.2.189. [DOI] [PubMed] [Google Scholar]
- Homma T., Kanki P. J., King N. W., Jr, Hunt R. D., O'Connell M. J., Letvin N. L., Daniel M. D., Desrosiers R. C., Yang C. S., Essex M. Lymphoma in macaques: association with virus of human T lymphotrophic family. Science. 1984 Aug 17;225(4663):716–718. doi: 10.1126/science.6087453. [DOI] [PubMed] [Google Scholar]
- Hu W. S., Temin H. M. Genetic consequences of packaging two RNA genomes in one retroviral particle: pseudodiploidy and high rate of genetic recombination. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1556–1560. doi: 10.1073/pnas.87.4.1556. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jones J. S., Allan R. W., Seufzer B., Temin H. M. Copackaging of different-sized retroviral genomic RNAs: little effect on retroviral replication or recombination. J Virol. 1994 Jun;68(6):4097–4103. doi: 10.1128/jvi.68.6.4097-4103.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kanki P. J., McLane M. F., King N. W., Jr, Letvin N. L., Hunt R. D., Sehgal P., Daniel M. D., Desrosiers R. C., Essex M. Serologic identification and characterization of a macaque T-lymphotropic retrovirus closely related to HTLV-III. Science. 1985 Jun 7;228(4704):1199–1201. doi: 10.1126/science.3873705. [DOI] [PubMed] [Google Scholar]
- Khan A. S., Martin M. A. Endogenous murine leukemia proviral long terminal repeats contain a unique 190-base-pair insert. Proc Natl Acad Sci U S A. 1983 May;80(9):2699–2703. doi: 10.1073/pnas.80.9.2699. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lander M. R., Chattopadhyay S. K. A Mus dunni cell line that lacks sequences closely related to endogenous murine leukemia viruses and can be infected by ectropic, amphotropic, xenotropic, and mink cell focus-forming viruses. J Virol. 1984 Nov;52(2):695–698. doi: 10.1128/jvi.52.2.695-698.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marx P. A., Maul D. H., Osborn K. G., Lerche N. W., Moody P., Lowenstine L. J., Henrickson R. V., Arthur L. O., Gilden R. V., Gravell M. Simian AIDS: isolation of a type D retrovirus and transmission of the disease. Science. 1984 Mar 9;223(4640):1083–1086. doi: 10.1126/science.6695196. [DOI] [PubMed] [Google Scholar]
- McLachlin J. R., Cornetta K., Eglitis M. A., Anderson W. F. Retroviral-mediated gene transfer. Prog Nucleic Acid Res Mol Biol. 1990;38:91–135. doi: 10.1016/s0079-6603(08)60709-6. [DOI] [PubMed] [Google Scholar]
- Miller A. D., Buttimore C. Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production. Mol Cell Biol. 1986 Aug;6(8):2895–2902. doi: 10.1128/mcb.6.8.2895. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miller A. D., Trauber D. R., Buttimore C. Factors involved in production of helper virus-free retrovirus vectors. Somat Cell Mol Genet. 1986 Mar;12(2):175–183. doi: 10.1007/BF01560664. [DOI] [PubMed] [Google Scholar]
- Morgan R. A., Nussbaum O., Muenchau D. D., Shu L., Couture L., Anderson W. F. Analysis of the functional and host range-determining regions of the murine ectropic and amphotropic retrovirus envelope proteins. J Virol. 1993 Aug;67(8):4712–4721. doi: 10.1128/jvi.67.8.4712-4721.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Muenchau D. D., Freeman S. M., Cornetta K., Zwiebel J. A., Anderson W. F. Analysis of retroviral packaging lines for generation of replication-competent virus. Virology. 1990 May;176(1):262–265. doi: 10.1016/0042-6822(90)90251-l. [DOI] [PubMed] [Google Scholar]
- Nabel G. J., Nabel E. G., Yang Z. Y., Fox B. A., Plautz G. E., Gao X., Huang L., Shu S., Gordon D., Chang A. E. Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11307–11311. doi: 10.1073/pnas.90.23.11307. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Oroszlan S., Barbacid M., Copeland T. D., Aaronson S. A., Gilden R. V. Chemical and Immunological characterization of the major structural protein (p28) of MMC-1, a rhesus monkey endogenous type C virus: homology with the major structural protein of avian reticuloendotheliosis virus. J Virol. 1981 Sep;39(3):845–854. doi: 10.1128/jvi.39.3.845-854.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ott D., Friedrich R., Rein A. Sequence analysis of amphotropic and 10A1 murine leukemia viruses: close relationship to mink cell focus-inducing viruses. J Virol. 1990 Feb;64(2):757–766. doi: 10.1128/jvi.64.2.757-766.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Otto E., Jones-Trower A., Vanin E. F., Stambaugh K., Mueller S. N., Anderson W. F., McGarrity G. J. Characterization of a replication-competent retrovirus resulting from recombination of packaging and vector sequences. Hum Gene Ther. 1994 May;5(5):567–575. doi: 10.1089/hum.1994.5.5-567. [DOI] [PubMed] [Google Scholar]
- Ou C. Y., Boone L. R., Yang W. K. A novel sequence segment and other nucleotide structural features in the long terminal repeat of a BALB/c mouse genomic leukemia virus-related DNA clone. Nucleic Acids Res. 1983 Aug 25;11(16):5603–5620. doi: 10.1093/nar/11.16.5603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pearson W. R., Lipman D. J. Improved tools for biological sequence comparison. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2444–2448. doi: 10.1073/pnas.85.8.2444. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rabin H., Benton C. V., Tainsky M. A., Rice N. R., Gilden R. V. Isolation and characterization of an endogenous type C virus of rhesus monkeys. Science. 1979 May 25;204(4395):841–842. doi: 10.1126/science.87013. [DOI] [PubMed] [Google Scholar]
- Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scadden D. T., Fuller B., Cunningham J. M. Human cells infected with retrovirus vectors acquire an endogenous murine provirus. J Virol. 1990 Jan;64(1):424–427. doi: 10.1128/jvi.64.1.424-427.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schwartzberg P., Colicelli J., Goff S. P. Construction and analysis of deletion mutations in the pol gene of Moloney murine leukemia virus: a new viral function required for productive infection. Cell. 1984 Jul;37(3):1043–1052. doi: 10.1016/0092-8674(84)90439-2. [DOI] [PubMed] [Google Scholar]
- Sorge J., Wright D., Erdman V. D., Cutting A. E. Amphotropic retrovirus vector system for human cell gene transfer. Mol Cell Biol. 1984 Sep;4(9):1730–1737. doi: 10.1128/mcb.4.9.1730. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Speck N. A., Baltimore D. Six distinct nuclear factors interact with the 75-base-pair repeat of the Moloney murine leukemia virus enhancer. Mol Cell Biol. 1987 Mar;7(3):1101–1110. doi: 10.1128/mcb.7.3.1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stoye J. P., Coffin J. M. The four classes of endogenous murine leukemia virus: structural relationships and potential for recombination. J Virol. 1987 Sep;61(9):2659–2669. doi: 10.1128/jvi.61.9.2659-2669.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Swain A., Coffin J. M. Mechanism of transduction by retroviruses. Science. 1992 Feb 14;255(5046):841–845. doi: 10.1126/science.1371365. [DOI] [PubMed] [Google Scholar]
- Tainsky M. A. Analysis of the virogenes related to the rhesus monkey endogenous type C retrovirus in monkeys and apes. J Virol. 1981 Mar;37(3):922–930. doi: 10.1128/jvi.37.3.922-930.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Temin H. M. Safety considerations in somatic gene therapy of human disease with retrovirus vectors. Hum Gene Ther. 1990 Summer;1(2):111–123. doi: 10.1089/hum.1990.1.2-111. [DOI] [PubMed] [Google Scholar]
- Torrent C., Gabus C., Darlix J. L. A small and efficient dimerization/packaging signal of rat VL30 RNA and its use in murine leukemia virus-VL30-derived vectors for gene transfer. J Virol. 1994 Feb;68(2):661–667. doi: 10.1128/jvi.68.2.661-667.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vanin E. F., Kaloss M., Broscius C., Nienhuis A. W. Characterization of replication-competent retroviruses from nonhuman primates with virus-induced T-cell lymphomas and observations regarding the mechanism of oncogenesis. J Virol. 1994 Jul;68(7):4241–4250. doi: 10.1128/jvi.68.7.4241-4250.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang J., Temin H. M. Rate and mechanism of nonhomologous recombination during a single cycle of retroviral replication. Science. 1993 Jan 8;259(5092):234–238. doi: 10.1126/science.8421784. [DOI] [PubMed] [Google Scholar]