Protection from lethal herpes simplex virus type 1 infection by vaccination with a UL41-deficient recombinant strain.

Abstract

The UL41 gene of herpes simplex virus type 1 (HSV-1) encodes a virion host shut off protein which is involved in immune evasion. The growth and virulence of HSV-1 is markedly reduced by the deletion of UL41. In this report, the UL41-deleted recombinant HSV-1 strain VR∆41 was evaluated as a prophylactic live attenuated vaccine against lethal HSV-1 infection in a mouse model. Intraperitoneal (i.p.) inoculation with the VR∆41 strain clearly inhibited lethal wild-type HSV-1 (VR-3 strain) infection after both i.p. and intracerebral (i.c.) inoculations. Vaccination with the VR∆41 strain was safer than VR-3 vaccination and was able to protect against a wild-type challenge to the same degree as VR-3 vaccination. In contrast, i.p. inoculation with ultraviolet-irradiated VR-3 induced resistance against i.p. infection, but not against i.c. Although replication of the VR∆41 strain in mice was greatly reduced compared to that of the VR-3 strain, VR∆41 strain maintained the ability to spread to the central nervous system (CNS) from a peripheral inoculation site. These results indicated that the VR∆41 strain evoked a potent immune reaction through viral protein expression within CNS without the induction of lethal encephalitis. The entry of antigens into the CNS was essential for the establishment of protective immunity against the lethal HSV encephalitis. We concluded that only a live attenuated vaccine is able to afford a prophylactic effect against CNS infection with HSV. In order to fulfill this requirement, UL41-deleted viruses provide a strong candidate for use as a recombinant live vaccine.