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Selective Up-Regulation of Intact, but Not Defective env RNAs of Endogenous Modified Polytropic Retrovirus by the Sgp3 Locus of Lupus-Prone Mice¹

Kumiko Yoshinobu^2,*, Lucie Baudino^2,*, Marie-Laure Santiago-Raber^*, Naoki Morito^*, Isabelle Dunand-Sauthier^*, Bernard J. Morley, Leonard H. Evans and Shozo Izui^3,*

^* Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Molecular Genetics and Rheumatology Section, Imperial College London, London, United Kingdom; and Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840

Endogenous retroviruses are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Because four different classes of endogenous retroviruses, i.e., ecotropic, xenotropic, polytropic, or modified polytropic (mPT), are expressed in mice, we investigated the possibility that a particular class of endogenous retroviruses is associated with the development of murine SLE. We observed >15-fold increased expression of mPT env (envelope) RNA in livers of all four lupus-prone mice, as compared with those of nine nonautoimmune strains of mice. This was not the case for the three other classes of retroviruses. Furthermore, we found that in addition to intact mPT transcripts, many strains of mice expressed two defective mPT env transcripts which carry a deletion in the env sequence of the 3' portion of the gp70 surface protein and the 5' portion of the p15E transmembrane protein, respectively. Remarkably, in contrast to nonautoimmune strains of mice, all four lupus-prone mice expressed abundant levels of intact mPT env transcripts, but only low or nondetectable levels of the mutant env transcripts. The Sgp3 (serum gp70 production 3) locus derived from lupus-prone mice was responsible for the selective up-regulation of the intact mPT env RNA. Finally, we observed that single-stranded RNA-specific TLR7 played a critical role in the production of anti-gp70 autoantibodies. These data suggest that lupus-prone mice may possess a unique genetic mechanism responsible for the expression of mPT retroviruses, which could act as a triggering factor through activating TLR7 for the development of autoimmune responses in mice predisposed to SLE.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Swiss National Foundation for Scientific Research. L.H.E. was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

² K.Y. and L.B. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Shozo Izui, Department of Pathology and Immunology, Centre Médical Universitaire, 1211 Geneva 4, Switzerland. E-mail address: Shozo.Izui{at}unige.ch

⁴ Abbreviations used in this paper: SLE, systemic lupus erythematosus; gp70 IC, gp70-anti-gp70 immune complexes; PT, polytropic; mPT, modified PT; WT, wild type; TBP, TATA-binding protein; LTR, long terminal repeat; UCR, upstream conserved region.