Targeting viral dsRNA for antiviral prophylaxis.
Double-stranded (ds)RNA in the infected cells is a trait shared by most if not all viruses. While humans have developed variable immune responses, viruses have also developed countermeasures to defeat dsRNA-induced antiviral strategies. Thus, we proposed a broad antiviral strategy to antagonize the countermeasures of viruses and bypass the dsRNA-induced signals that are readily defeated by viruses. By rewiring the dsRNA-binding proteins in the dsRNA complex and reconnecting them to apoptosis signaling, we created several dsRNA-dependent caspase recruiters, termed dsCAREs, to bypass dsRNA-induced antiviral signals that would otherwise be targeted by viruses. Adenovirus and vesicular stomatitis virus, representing viruses of the dsDNA and negative-stranded RNA viral groups, were used to infect HEK293 cells. The dsCARE chimera was added in medium to evaluate its antiviral activity. The truncated dsCAREs were used as controls. We demonstrate that dsCARE suppresses viral infection starting at 0.1 μg/ml and reaches the peak at 2 μg/ml. The EC(50) was ∼0.2 μg/ml. However, it had an undetectable effect on uninfected cells. Further data show that both dsRNA binding and apoptosis activation of dsCARE are essential for its antiviral activity. We conclude that dsRNA is a practical virus-associated molecular pattern that can be targeted for broad and rapid antiviral prophylaxis.
Fei
Zhou
Z
Department of Surgery, Boston Veterans Affairs Healthcare System, Boston University School of Medicine, Boston, Massachusetts 02130, USA.
Liu
Yang
Y
Yan
Zhen
Z
Fan
Daiming
D
Alexander
Alice
A
Yang
Jing-Hua
JH
D000243:Adenosine Deaminase / Q000235:genetics; D000256:Adenoviridae / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D011485:Protein Binding; D012330:RNA, Double-Stranded / Q000235:genetics*; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D018116:Vesiculovirus / Q000187:drug effects
D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D004247:DNA; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase