C7L-based Tumor Selectivity Enhancement of Oncolytic Vaccinia Virus
Oncolytic vaccinia virus (VACV) can specifically target and lyse tumor cells, and induce anti-tumor effects through various mechanisms. With years of working experience in immunology and oncology, Creative Biolabs has established a comprehensive OncoVirapy™ platform to provide a full range of gene manipulation methods for the development of the vaccinia virus (VV) to meet your project needs. Here is a general strategy.
Brief Introduction of C7L Gene
VV has a very wide host range and it can infect many vertebrate animal species. The host range can be significantly narrowed by deleting the host range genes, the most important genes are E3L, K1L, and C7L. C7L is the second host range gene that can compensate for K1L function in human cells, but not in rabbit cells. K1L and C7L support VV replication by antagonizing some antiviral factors, which are expressed constitutively in most mammalian cells but only induced by IFN only in some cell lines.
Scientists reported that C7L has an anti-apoptotic function, and both K1L and C7L can inhibit the antiviral effectors induced by type I interferons and interferon regulatory factor 1 (IRF1). K1L and C7L have the same function in supporting VV replication but share no sequence similarity. The C7L family of host range genes is essential for poxviruses to replicate in mammalian hosts, and the function of C7L is evolutionally conserved in all poxviruses.
Fig.1 The structure of VACV C7 displays a previously unidentified fold. (Meng, 2015)
VV with Deletion or Mutation in the C7L Gene
- VV Replication
- Interferon Antagonist
- Immunoregulation
Deletion both of C7L and K1L leads to deficient replication on mammalian cells and decreased virulence in mice. C7L gene was also required for vaccinia virus Tian Tan (VTT) to replicate and disseminate in BHK-21 cells.
Scientists found that K1L and C7L play an essential and nonredundant role in blocking the antiviral effects of IFNs. They can be used as novel IFN antagonists, functioning differently than the IFN antagonists previously identified in the VV.
Type 1 IFNs are potent inhibitors of viral replication and are induced in most mammalian cells infected by viruses through Toll-like receptors, RIG-I/MDA5 RNA receptors, and DNA sensors. Type I IFNs play a critical role in innate immune defense against viruses and in modulating the adaptive immune response to infection and tumor formation.
To detect the influence of host range gene deletion on immunogenicity, scientists found that the deletion of C7L or K1L decreases vaccinia-specific humoral responses but has no effect on cellular immune responses in BALB/c mice. C7L and K1L deleted VTT recombinants with HIV genes induced strong cellular and humoral immune responses against HIV genes in BALB/c mice.
It was further demonstrated that infection with VV variants lacking C7L and K1L enhanced phosphorylation of eukaryotic translation initiation factor 2a (eIF2a), and the deletion of C7L and K1L attenuates VV's ability to induce body weight loss and greatly attenuates virus neurovirulence in BALB/c mice.
With our well-established VACV engineering platform, the experienced scientists at Creative Biolabs are dedicated to helping you develop a strategy to manipulate the VACV for your project requirements.
Reference
- Meng, X.; et al. Structural basis for antagonizing a host restriction factor by C7 family of poxvirus host-range proteins. Proc Natl Acad Sci U S A. 2015, 112: 14858-63.