Disruption of Virion Host Shutoff Activity Improves the Immunogenicity and Protective Capacity of a Replication-Incompetent Herpes Simplex Virus Type 1 Vaccine Strain

ABSTRACT The virion host shutoff (vhs) protein encoded by herpes simplex virus type 1 (HSV-1) destabilizes both viral and host mRNAs. An HSV-1 strain with a mutation in vhs is attenuated in virulence and induces immune responses in mice that are protective against corneal infection with virulent HSV-1, but it has the capacity to establish latency. Similarly, a replication-incompetent HSV-1 strain with a mutation in ICP8 elicits an immune response protective against corneal challenge, but it may be limited in viral antigen production. We hypothesized therefore that inactivation of vhs in an ICP8− virus would yield a replication-incompetent mutant with enhanced immunogenicity and protective capacity. In this study, a vhs−/ICP8− HSV-1 mutant was engineered. BALB/c mice were immunized with incremental doses of the vhs−/ICP8− double mutant or vhs−or ICP8− single mutants, or the mice were mock immunized, and protective immunity against corneal challenge with virulent HSV-1 was assessed. Mice immunized with the vhs−/ICP8− mutant showed prechallenge serum immunoglobulin G titers comparable to those immunized with replication-competent vhs− virus and exceed those of mice immunized with the ICP8− single mutant. Following corneal challenge, the degrees of protection against ocular disease, weight loss, encephalitis, and establishment of latency were similar for vhs−/ICP8− and vhs−virus-vaccinated mice. Moreover, the double deleted vhs−/ICP8− virus protected mice better in all respects than the single deleted ICP8− mutant virus. The data indicate that inactivation of vhs in a replication-incompetent virus significantly enhances its protective efficacy while retaining its safety for potential human vaccination. Possible mechanisms of enhanced immunogenicity are discussed.