Abstract
The human cytomegalovirus (HCMV) clinical strain Toledo and the attenuated strain AD169 exhibit a striking difference in pathogenic potential and cell tropism. The virulent Toledo genome contains a 15-kb segment, which is present in all virulent strains but is absent from the AD169 genome. The pathogenic differences between the 2 strains are thought to be associated with this additional genome segment. Cytokines induced during viral infection play major roles in the regulation of the cellular interactions involving cells of the immune and inflammatory systems and consequently determine the pathogenic outcome of infection. The chemokine RANTES (Regulated on activation, normal T-cell expressed and secreted) attracts immune cells during inflammation and the immune response, indicating a role for RANTES in viral pathogenesis. Here, we show that RANTES was downregulated in human foreskin fibroblast (HFF) cells at a later stage after infection with the Toledo strain but not after infection with the AD169 strain. miR-UL148D, the only miRNA predicted from the UL/b' sequences of the Toledo genome, targeted the 3′-untranslated region of RANTES and induced degradation of RANTES mRNA during infection. While wild-type Toledo inhibited expression of RANTES in HFF cells, Toledo mutant virus in which miR-UL148D is specifically abrogated did not repress RANTES expression. Furthermore, miR-UL148D-mediated downregulation of RANTES was inhibited by treatment with a miR-UL148D-specific inhibitor designed to bind to the miR-UL148D sequence via an antisense mechanism, supporting the potential value of antisense agents as therapeutic tools directed against HCMV. Our findings identify a viral microRNA as a novel negative regulator of the chemokine RANTES and provide clues for understanding the pathogenesis of the clinical strains of HCMV.
Highlights
Human cytomegalovirus (HCMV) is a member of the bherpesvirus family and a ubiquitous human pathogen
RANTES secretion is reduced by the attenuated HCMV strain AD169 in human foreskin fibroblast (HFF) cells during the replication phase [27]
Taking diverse roles of RANTES in immune and inflammatory responses into consideration and better understanding the virulence and pathogenicity of the clinical HCMV strain, we tested whether RANTES expression is regulated by Toledo, which is the predominant clinical isolate of HCMV
Summary
Human cytomegalovirus (HCMV) is a member of the bherpesvirus family and a ubiquitous human pathogen. Injection of the low-passaged HCMV strain Toledo into healthy adults causes clinically apparent diseases [4], whereas adults inoculated with the attenuated HCMV AD169 or Towne strains do not manifest any clinical symptoms [5,6]. Clinical strains confer a strong NK cell resistance, whereas high-passaged attenuated strains cause only marginal effects with respect to NK cell recognition [7,8]. An additional 19 viral genes (UL133 through UL151), which are absent from AD169, were found in lowpassaged clinical isolates [10] These genetic differences between attenuated strains and clinical strains may be implicated in HCMV-induced immunopathogenesis, as well as in strain-specific behaviors, such as tissue tropism and the ability to establish persistent or latent infections [11,12,13]
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