S. Hodge et al., Induction of Fas ligand expression by an acutely lethal simian immunodeficiency virus, SIVsmmPBj14, VIROLOGY, 252(2), 1998, pp. 354-363
Simian immunodeficiency virus strain PBj14, SIVsmmPBj14, is unique among pr
imate lentiviruses in its ability to trigger the proliferation of resting s
imian lymphocytes and to cause the rapid death of experimentally inoculated
pigtailed macaques. Severe enteropathy, immune activation, and extensive a
poptosis, particularly within gut-associated lymphoid tissue, characterize
the acute disease syndrome associated with SIVsmmPBj14 infection. In the pr
esent study, we examined whether the ability of this virus to cause widespr
ead apoptosis might be linked to the up-regulation of Fas ligand (CD95L) ex
pression in virally infected cells. In vitro studies revealed that expressi
on of the viral Nef protein, in the absence of any other viral gene product
, was sufficient to up-regulate the transcriptional activity of the CD95L p
romoter and to cause cell surface expression of Fas ligand. This up-regulat
ion was NFAT dependent (inhibited by cyclosporin A) and did not occur in ce
lls that expressed a mutated derivative of the viral Nef protein, lacking a
previously defined immunoreceptor tyrosine-based activation motif. These f
indings were corroborated by analysis of tissue sections from virally infec
ted macaques. Immunohistochemical staining revealed that Fas ligand express
ion was efficiently up-regulated in the GALT of animals that had been exper
imentally infected with wild-type SIVsmmPBj14 but not in animals that were
infected with a nonacutely pathogenic viral mutant lacking the Nef ITAM. Ta
ken together, these results suggest that the ability of SIVsmmPBj14 to caus
e acutely lethal disease and to up-regulate Fast expression may be linked.
Additional studies will be required to determine whether the induction of F
ast expression is in itself important for acute disease pathogenesis, (C) 1
998 Academic Press.