Summary auto-generated
This study investigates how cyclosporin A (CsA) inhibits vaccinia virus (VV) replication by examining whether cyclophilins (Cyps), the cellular proteins that bind CsA, are involved in its antiviral activity. Researchers tested six CsA analogues with varying affinities for Cyps in VV-infected monkey kidney cells (BSC-40). Using Sephadex column assays and affinity chromatography, they measured each analogue's binding to Cyps, particularly the major isoform CypA. They then evaluated how each analogue affected VV production. The results demonstrated a clear correlation: analogues with strong cyclophilin-binding activity (CsC, CsG, [MeAla6]CsA) potently inhibited VV replication, reducing virus yield by 73-99%, while analogues with weak ([MeBm2t1]CsA, CsH) or no ([MeLeu11]CsA) Cyp binding showed minimal antiviral effects. The researchers also confirmed that CsA analogues reduced accumulation of viral DNA, proteins, and late gene expression. These findings suggest that cyclophilins play an essential role in the VV replication cycle and that CsA's antiviral mechanism differs from its immunosuppressive pathway, likely involving inhibition of cyclophilin isomerase activity required for proper protein folding and trafficking.
Key findings
- Strong cyclophilin-binding CsA analogues (CsC, CsG, [MeAla6]CsA) inhibited vaccinia virus replication by 73-99%, while weak or non-binding analogues had minimal antiviral effects.
- A direct correlation exists between an analogue's affinity for cyclophilins (particularly CypA) and its ability to inhibit VV production.
- CsA's antiviral mechanism against vaccinia virus appears distinct from its immunosuppressive pathway, which involves calcineurin inhibition rather than cyclophilin binding.
- Cyclophilins are required during the vaccinia virus replication cycle, as blocking their peptidyl-prolyl isomerase activity impairs viral DNA and protein accumulation.
- Virus yield inhibition correlates with reduced accumulation of viral DNA, proteins, and late gene expression in treated cells.
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Abstract
The mechanism by which cyclosporin A (CsA) inhibits vaccinia virus (VV) replication is still unclear. The present study addresses the question of whether CsA-binding proteins named cyclophilins (Cyps) are involved in the anti-VV activity of CsA. Six CsA analogues were analysed, and their affinity for Cyps in VV-infected BSC-40 cells and their potency as inhibitors of VV replication were evaluated. It was demonstrated that analogues with strong Cyp-binding activity, such as CsC, CsG and [MeAla6]CsA, also exhibit a strong antiviral effect. In contrast, drugs with low ([MeBm2t1]CsA and CsH) or no ([MeLeu11]CsA) affinity for Cyps show poor or no antiviral activity. The data obtained suggest a correlation between the ability of CsA to block VV replication and Cyp binding activity, and indicate the involvement of Cyps in the VV replicative cycle. They also suggest that the anti-VV action of CsA may occur by a pathway distinct from that involved in the immunosuppressive effect of the drug.