title: An attenuated herpes simplex virus type 1 (HSV1) encoding the HIV-1 Tat protein protects mice from a deadly mucosal HSV1 challenge.
abstract: Herpes simplex virus types 1 and 2 (HSV1 and HSV2) are common infectious agents in both industrialized and developing countries. They cause recurrent asymptomatic and/or symptomatic infections, and life-threatening diseases and death in newborns and immunocompromised patients. Current treatment for HSV relies on antiviral medications, which can halt the symptomatic diseases but cannot prevent the shedding that occurs in asymptomatic patients or, consequently, the spread of the viruses. Therefore, prevention rather than treatment of HSV infections has long been an area of intense research, but thus far effective anti-HSV vaccines still remain elusive. One of the key hurdles to overcome in anti-HSV vaccine development is the identification and effective use of strategies that promote the emergence of Th1-type immune responses against a wide range of epitopes involved in the control of viral replication. Since the HIV1 Tat protein has several immunomodulatory activities and increases CTL recognition of dominant and subdominant epitopes of heterologous antigens, we generated and assayed a recombinant attenuated replication-competent HSV1 vector containing the tat gene (HSV1-Tat). In this proof-of-concept study we show that immunization with this vector conferred protection in 100% of mice challenged intravaginally with a lethal dose of wild-type HSV1. We demonstrate that the presence of Tat within the recombinant virus increased and broadened Th1-like and CTL responses against HSV-derived T-cell epitopes and elicited in most immunized mice detectable IgG responses. In sharp contrast, a similarly attenuated HSV1 recombinant vector without Tat (HSV1-LacZ), induced low and different T cell responses, no measurable antibody responses and did not protect mice against the wild-type HSV1 challenge. These findings strongly suggest that recombinant HSV1 vectors expressing Tat merit further investigation for their potential to prevent and/or contain HSV1 infection and dissemination.
authors.affiliation: Department of Life Sciences and Biotechnology, Section of Applied Microbiology and Pathology, University of Ferrara, Ferrara, Italy; Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Mariaconcetta
authors.initials: M
authors.lastname: Sicurella
authors.affiliation: Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicoli
authors.affiliation: Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gallerani
authors.affiliation: Department of Life Sciences and Biotechnology, Section of Applied Microbiology and Pathology, University of Ferrara, Ferrara, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Volpi
authors.affiliation: Department of Life Sciences and Biotechnology, Section of Applied Microbiology and Pathology, University of Ferrara, Ferrara, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Berto
authors.affiliation: Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Finessi
authors.affiliation: Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy; Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Destro
authors.affiliation: Department of Life Sciences and Biotechnology, Section of Applied Microbiology and Pathology, University of Ferrara, Ferrara, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Manservigi
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Cafaro
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ensoli
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Caputo
authors.affiliation: Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Gavioli
authors.affiliation: Department of Life Sciences and Biotechnology, Section of Applied Microbiology and Pathology, University of Ferrara, Ferrara, Italy.
authors.forename: Peggy C
authors.initials: PC
authors.lastname: Marconi
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D002460:Cell Line; D002522:Chlorocebus aethiops; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D006367:HeLa Cells; D006561:Herpes Simplex / Q000517:prevention & control*; D022301:Herpes Simplex Virus Vaccines / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007763:Lac Operon / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014611:Vaccination; D014709:Vero Cells; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D018984:Epitopes, T-Lymphocyte; D022301:Herpes Simplex Virus Vaccines; D007074:Immunoglobulin G; D054322:tat Gene Products, Human Immunodeficiency Virus