A glucocorticoid response element in the LTR U3 region of Friend murine leukaemia virus variant FIS-2 enhances virus production in vitro and is a major determinant for sex differences in susceptibility to FIS-2 infection in vivo.
The nucleotide sequence of the Friend murine leukaemia virus variant FIS-2 LTR has high identity with the closely related Friend murine leukaemia virus (F-MuLV) LTR, except for the deletion of one direct repeat, a few point mutations and the generation of a glucocorticoid response element (GRE) in the U3 region. The GRE can mediate gene induction by glucocorticoids, mineral corticoids, progesterone and androgens, and it has been shown that incorporation of a GRE(s) within the LTR can increase the transcriptional activity of retroviral enhancers. We have previously reported an increased early virus replication in male mice compared with female mice when infected with a virus containing the FIS-2 LTR and have proposed that the GRE might contribute to this sex difference. In the present study, we introduced a single point mutation in the GRE and performed comparative studies in NIH 3T3 cells and in young adult male and female NMRI mice. We found that significantly more virus was produced from NIH 3T3 cells infected with wt FIS-2 than from cells infected with the FIS-2 GRE mutant and that this difference was further augmented by glucocorticoids. The glucocorticoid antagonist RU486 inhibited virus production in a dose-dependent manner. The wt FIS-2 disseminated significantly faster than the FIS-2 GRE mutant in both male and female mice. There was no significant difference in the dissemination rate between male and female mice infected with the FIS-2 GRE mutant. Hence, the GRE in the FIS-2 LTR is one determinant of the significant sex difference in susceptibility to FIS-2 infection.
Bruland
Torunn
T
Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, MTFS Olav Kyrresg. 3, N-7489 Trondheim, Norway.
Lavik
Liss Anne S
LAS
St Olavs Hospital HF, Trondheim, Norway.
Dai
Hong Yan
HY
St Olavs Hospital HF, Trondheim, Norway.
Dalen
Are
A
St Olavs Hospital HF, Trondheim, Norway.|Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, MTFS Olav Kyrresg. 3, N-7489 Trondheim, Norway.
D016475:3T3 Cells; D000818:Animals; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000821:virology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005622:Friend murine leukemia virus / Q000235:genetics / Q000472:pathogenicity; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D007942:Leukemia, Experimental / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D009154:Mutation; D020218:Response Elements / Q000502:physiology*; D012192:Retroviridae Infections / Q000473:pathology / Q000821:virology*; D012737:Sex Factors; D020079:Terminal Repeat Sequences; D014412:Tumor Virus Infections / Q000473:pathology / Q000821:virology*; D014774:Virulence; D014779:Virus Replication / Q000187:drug effects
D005938:Glucocorticoids; D006727:Hormone Antagonists; D015735:Mifepristone