Abstract
Bovine herpesvirus 4 (BoHV-4) is a promising vector for the delivery and intracellular expression of recombinant antigens and can thus be considered as a new prototype vaccine formulation system. An interesting, and actively pursued, antigen in the context of human immunodeficiency virus (HIV) infection prophylaxis (and therapy) is the C–C chemokine receptor type 5 (CCR5) co-receptor, whose blockage by specific antibodies has been shown to inhibit both viral entry and cell-to-cell transmission of the virus. Building on our previous work on the BoHV-4 vector system, we have engineered and tested a replication-competent derivative of BoHV-4 (BoHV-4-CMV-hCCR5ΔTK) bearing a human CCR5 (hCCR5) expression cassette. We show here that CCR5 is indeed expressed at high levels in multiple types of BoHV-4-CMV-hCCR5ΔTK-infected cells. More importantly, two intravenous inoculations of CCR5-expressing BoHV-4 virions into rabbits led to the production of anti-CCR5 antibodies capable of reacting with the CCR5 receptor exposed on the surface of HEK293T cells through specific recognition of the amino-terminal region (aa 14–34) of the protein. Given the growing interest for anti-CCR5 immunization as an HIV control strategy and the many advantages of virus-based immunogen formulations (especially for poorly immunogenic or self-antigens), the results reported in this study provide preliminary validation of BoHV-4 as a safe viral vector suitable for CCR5 vaccination.
Highlights
Bovine herpesvirus 4 (BoHV-4) is dsDNA genome virus belonging to Herpesviridae family, Gammaherpesvirus subfamily and Rhadinovirus genus
Recombinant BoHV-4, derived from the cloned BoHV-4 genome in the form of a bacterial artificial chromosome (BAC), able to express immune-dominant antigens derived from different pathogens was successfully used for immunization purposes in the abovementioned non-natural host species without any apparent detrimental effect, overt clinical sign or pathology causally related to viral vector inoculation [2, 4, 5, 7,8,9,10,11]
Evident oncolytic properties in immune-competent orthotopic syngeneic mouse and rat glioma models were correlated to the herpes simplex virus-1 thymidine kinase (HSV-1-TK) gene included into BoHV-4-based vector genome [6]
Summary
Bovine herpesvirus 4 (BoHV-4) is dsDNA genome virus belonging to Herpesviridae family, Gammaherpesvirus subfamily and Rhadinovirus genus. Ex vivo infection of non-human primate tissue explants has been observed (paper in preparation) This feature suggests the use of BoHV-4 as a potentially competent viral vector for in vivo human cell transduction as well. Because of its role as a virus co-receptor, CCR5 represents a very attractive target for preventing/controlling HIV infection and multiple anti-HIV strategies centered on this receptor are being developed [13]. These include small-molecule CCR5 antagonists approved for clinical use such as Aplaviroc (GlaxoSmithKline), Maraviroc (Pfizer), and Vicriviroc (Schering-Plough). We document the capability of an engineered BoHV-4 vector to deliver and express a human CCR5 (hCCR5) expression cassette in rabbits
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