Strategies for retargeting oncolytic HSV-1. (IMAGE)
Caption
A) gD modification for retargeting: Retargeting is achieved by inserting specific single-chain variable fragments (scFvs) into gD genes with deletions at amino acid (AA) positions 6–38. These modifications block the interaction between gD and its natural receptors, redirecting the virus to target cells expressing the corresponding receptor for the inserted scFv. Binding of the scFv-gD chimera to the new receptor activates gD, which transmits the activation signal to gH/gL and subsequently to gB, triggering viral fusion with the host cell membrane. The precise role of gB's receptor in facilitating entry, through either pre- or post-fusion forms, remains unclear.
(B) gH modification for retargeting: Retargeting is accomplished by inserting specific scFvs between residues 23 and 24 of gH, enabling the virus to target cells expressing specific receptors. Concurrently, deletion of gD residues 6–38 prevents the interaction with natural gD receptors. In the absence of gD receptor activation, the interaction of the chimeric scFv-gH with specific receptors and integrins activates gH/gL, which subsequently activates gB, leading to fusion of the viral and host cell membranes.
(C) gB modification for retargeting: Redirection consists of the insertion of anti-HER2 scFv at amino acid 42 (AA) at gB while removing gD residues 6–38 to prevent off-target interactions with gD native receptors. The interaction of the chimeric gB-HER2 with HER2 receptors directly activates gB, triggering membrane fusion and repositioning the virus's tropism to HER2-positive cells.
(D) Retargeting via soluble adaptor molecules: The soluble adapter molecule consists of two functional domains: one end binds to HVEM in HSV gD, and the other end binds to a specific target receptor HER2 on host cells. Heavy targeting was achieved by inserting an expression cassette for the adapter HVEM-scFvHER2 in the UL3-UL4 intergenic region, while an open reading frame for anti-HER2scFv was inserted into residue 29 of gH. When adaptor proteins are properly synthesized and secreted, linkers bind to gD, and the target receptor HER2 activates gH/gL, then relays the activation signal to gB, and initiates fusion of the viral membrane with the host cell membrane.
Credit
Yufang Zou, Juan Tao, Yingzheng Gao, Jixuan Wang, Pengfei Wang, Jingyuan Yan, Zuqing Nie, Dewei Jiang, Xinwei Huang
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