Construction and properties of a herpes simplex virus 2 dl5-29 vaccine candidate strain encoding an HSV-1 virion host shutoff protein.
Abstract
The replication-defective herpes simplex virus 2 (HSV-2) dl5-29 mutant virus strain with deletions in the U(L)5 and U(L)29 genes has been shown to protect mice and guinea pigs against challenge with wild-type (wt) HSV-2 and to protect against ocular disease caused by HSV-1 infection. The dl5-29 strain is currently being prepared for clinical trials as a herpes vaccine candidate. As a possible approach to improve the efficacy of dl5-29 as a genital herpes vaccine, we replaced the U(L)41 gene encoding the virion host shutoff function (vhs) with the U(L)41 gene from HSV-1. While the HSV-2 U(L)41 and HSV-1 U(L)41 gene products have analogous functions, vhs-1 is 40-fold less active than vhs-2. Previously, it was shown that disruption of the U(L)41 gene can increase the efficacy of dl5-29 as a vaccine against HSV-2. These properties led us to hypothesize that replacement of vhs-2 by vhs-1 would decrease cytopathic effects in infected host cells, allowing longer survival of antigen-presenting cells and induction of stronger immune responses. The new recombinant dl5-29-41.1 virus shows nearly the same immunogenicity and protection against HSV-2 challenge as the parental dl5-29 virus or a triply deleted mutant virus, dl5-29-41, in the m...Continue Reading
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