Targeting of Kaposi’s sarcoma-associated herpesvirus by immunotoxins directed against the viral G protein-coupled receptor, ORF74 - 04/02/26
Abstract |
Background and purpose |
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a common virus with severe outcome and no effective antiviral treatment. KSHV encodes the constitutive active chemokine receptor ORF74 with broad-spectrum CXC-chemokine binding. Here, we leverage ORF74’s mimic of endogenous receptors to design chemokine-based immunotoxins for selective killing of KSHV-infected cells.
Experimental approach |
Four CXC-chemokines with high affinity to ORF74 were fused to domain II, IB, and III of Pseudomonas exotoxin A to generate fusion toxin proteins (FTPs). FTP-induced cell killing was tested in cells expressing ORF74 or one of four chemokine receptors (CXCR1–4). Internalization of all receptors was probed using SNAP-tagged receptors. Second-generation FTPs were designed from receptor structures and molecular modelling to increase selectivity for ORF74 over CXCR1–4. Finally, antiviral activity of FTPs was tested using genetically engineered KSHV.
Key results |
FTPs, based on the agonists (CXCL1, and −8) and inverse agonists (CXCL10 and −12) of ORF74 potently killed ORF74-expressing cells. The inverse agonist based FTPs leveraged constitutive internalization for efficient toxin delivery via ORF74, whereas agonists increased internalization further. CXCL10-FTP had the strongest cell-killing and, as the only FTP, selectivity for ORF74 over its endogenous receptor, CXCR3. Second-generation FTPs improved this selectivity from 25-fold to 126-fold by the mutation (R8D) in CXCL10-FTP, designed to lose ionic interaction within CXCR3’s main binding pocket. Both inverse agonist-based FTPs effectively prevented KSHV-reactivation.
Conclusion and implications |
Our findings highlight the versatility of FTPs in precise delivery of toxin payloads and provide a foundation for potential applications in antiviral and anticancer therapies targeting KSHV-associated diseases.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Kaposi’s sarcoma-associated herpesvirus (KSHV) is widespread and oncogenic. |
• | Infections with KSHV and related diseases lack effective treatment. |
• | KSHV encodes the constitutive active receptor ORF74, binding many CXC-chemokines. |
• | Endogenous chemokines hijacking inspired the fusion toxin proteins (FTPs) design. |
• | Our FTPs target ORF74, allowing selective killing of KSHV-infected cells. |
Keywords : Kaposi Sarcoma-associated Herpesvirus (KSHV), Cancer, ORF74, Immunotoxins, Chemokine receptors
Plan
Vol 195
Article 118797- février 2026 Retour au numéro
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