title: 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 murine model of infection, and grows to higher titers than the parental strain in complementing cells, which is important for GMP production. The results have implications for the design of future HSV-2 vaccine candidates and mechanisms of induction of protective immunity against genital herpes.
authors.affiliation: Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Natalia J
authors.initials: NJ
authors.lastname: Reszka
authors.forename: Timothy
authors.initials: T
authors.lastname: Dudek
authors.forename: David M
authors.initials: DM
authors.lastname: Knipe
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D005260:Female; D006558:Herpes Genitalis / Q000276:immunology / Q000517:prevention & control*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology*; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000276:immunology*; D022283:Herpesvirus Vaccines / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011995:Recombination, Genetic; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D022283:Herpesvirus Vaccines; C413084:UL29 protein, Herpes simplex virus type 2; C081688:Ul41 protein, Human herpesvirus 1; D014613:Vaccines, Attenuated; D014764:Viral Proteins; C064566:herpes simplex virus type 2 protein UL41