Disruption of virion host shutoff activity improves the immunogenicity andprotective capacity of a replication-incompetent herpes simplex virus type1 vaccine strain

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 mu tation in vhs is attenuated in virulence and induces immune responses in mi ce that are protective against corneal infection with virulent HSV-1, but i t has the capacity to establish latency. Similarly, a replication-incompete nt HSV-1 strain with a mutation in ICP8 elicits an immune response protecti ve against corneal challenge, but it may be limited in viral antigen produc tion. We hypothesized therefore that inactivation of vhs in an ICP8(-) viru s 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 wer e mock immunized, and protective immunity against corneal challenge with vi rulent HSV-1 was assessed. Mice immunized with the vhs(-)/ICP8(-) mutant sh owed prechallenge serum immunoglobulin G titers comparable to those immuniz ed with replication-competent vhs- virus and exceed those of mice immunized with the ICP8(-) single mutant. Following corneal challenge, the degrees o f protection against ocular disease, weight loss, encephalitis, and establi shment of latency were similar for vhs(-)/ICP8(-) and vhs(-) virus-vaccinat ed mice. Moreover, the double deleted vhs(-)/ICP8(-) virus protected mice b etter in all respects than the single deleted ICP8(-) mutant virus. The dat a indicate that inactivation of vhs in a replication-incompetent virus sign ificantly enhances its protective efficacy while retaining its safety for p otential human vaccination. Possible mechanisms of enhanced immunogenicity are discussed.