Hodge S, Novembre F J, Whetter L, Gelbard H A, Dewhurst S
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, 14642, USA.
Virology. 1998 Dec 20;252(2):354-63. doi: 10.1006/viro.1998.9477.
Simian immunodeficiency virus strain PBj14, SIVsmmPBj14, is unique among primate lentiviruses in its ability to trigger the proliferation of resting simian lymphocytes and to cause the rapid death of experimentally inoculated pigtailed macaques. Severe enteropathy, immune activation, and extensive apoptosis, particularly within gut-associated lymphoid tissue, characterize the acute disease syndrome associated with SIVsmmPBj14 infection. In the present study, we examined whether the ability of this virus to cause widespread apoptosis might be linked to the up-regulation of Fas ligand (CD95L) expression in virally infected cells. In vitro studies revealed that expression 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 promoter and to cause cell surface expression of Fas ligand. This up-regulation was NFAT dependent (inhibited by cyclosporin A) and did not occur in cells that expressed a mutated derivative of the viral Nef protein, lacking a previously defined immunoreceptor tyrosine-based activation motif. These findings were corroborated by analysis of tissue sections from virally infected macaques. Immunohistochemical staining revealed that Fas ligand expression was efficiently up-regulated in the GALT of animals that had been experimentally infected with wild-type SIVsmmPBj14 but not in animals that were infected with a nonacutely pathogenic viral mutant lacking the Nef ITAM. Taken together, these results suggest that the ability of SIVsmmPBj14 to cause acutely lethal disease and to up-regulate FasL expression may be linked. Additional studies will be required to determine whether the induction of FasL expression is in itself important for acute disease pathogenesis.
猿猴免疫缺陷病毒株PBj14，即SIVsmmPBj14，在灵长类慢病毒中独一无二，它能够触发静息猿猴淋巴细胞的增殖，并导致实验接种的猪尾猕猴迅速死亡。严重的肠道病、免疫激活以及广泛的细胞凋亡，尤其是在肠道相关淋巴组织内，是与SIVsmmPBj14感染相关的急性疾病综合征的特征。在本研究中，我们检测了这种病毒引发广泛细胞凋亡的能力是否可能与病毒感染细胞中Fas配体（CD95L）表达的上调有关。体外研究表明，在没有任何其他病毒基因产物的情况下，病毒Nef蛋白的表达足以上调CD95L启动子的转录活性，并导致Fas配体在细胞表面表达。这种上调依赖于NFAT（被环孢菌素A抑制），并且在表达病毒Nef蛋白突变衍生物的细胞中不发生，该突变衍生物缺乏先前定义的基于免疫受体酪氨酸的激活基序。对病毒感染猕猴的组织切片分析证实了这些发现。免疫组织化学染色显示，在实验感染野生型SIVsmmPBj14的动物的肠道相关淋巴组织中，Fas配体表达有效上调，但在感染缺乏Nef ITAM的非急性致病性病毒突变体的动物中则没有上调。综上所述，这些结果表明SIVsmmPBj14导致急性致死性疾病和上调FasL表达的能力可能有关联。需要进一步的研究来确定FasL表达的诱导本身是否对急性疾病发病机制很重要。
