title: Systemic immunodominant CD8 responses with an effector-like phenotype are induced by intravaginal immunization with attenuated HSV vectors expressing HIV Tat and mediate protection against HSV infection.
abstract: Mucosal HSV infection remains a public health issue in developing and developed world. However, an effective vaccine is still missing, partly because of the incomplete knowledge of correlates of protection. In this study we have investigated the kinetics and quality of immunity elicited by an attenuated HSV1 vector expressing the immunomodulatory Tat protein of HIV-1 (HSV1-Tat). Animals were immunized by intravaginal (IVag) or intradermal (ID) route with HSV1-Tat or with a control HSV1 vector expressing the LacZ gene (HSV1-LacZ) and immune responses were characterized in different anatomical districts. IVag immunization with HSV1-Tat enhanced both expansion and memory phases of HSV-specific immunodominant CD8 responses at systemic, but not local, level and induced short- and long-term protection against mucosal challenge. Conversely, ID immunization with HSV1-Tat favored HSV-subdominant CD8 responses, which protected mice only at early time points after immunization. IVag immunization, in particular with HSV1-Tat, compared to ID immunization, induced the differentiation of CD8(+) T lymphocytes into short-lived effector (SLEC) and effector memory (Tem) cells, generating more robust recall responses associated with increased control of virus replication. Notably, systemic SLEC and Tem contributed to generate protective local secondary responses, demonstrating their importance for mucosal control of HSV. Finally, IgG responses were observed mostly in IVag HSV1-Tat immunized animals, although seemed dispensable for protection, which occurred even in few IgG negative mice. Thus, HSV1 vectors expressing Tat induce protective anti-HSV1 immune responses.
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicoli
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gallerani
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Skarlis
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Mariaconcetta
authors.initials: M
authors.lastname: Sicurella
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Cafaro
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, Roma, 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, University of Ferrara, Ferrara, Italy.
authors.forename: Peggy C
authors.initials: PC
authors.lastname: Marconi
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy. Electronic address: r.gavioli@unife.it.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Gavioli
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006561:Herpes Simplex / Q000517:prevention & control*; D018259:Herpesvirus 1, Human; D022283:Herpesvirus Vaccines / Q000276:immunology*; D018928:Immunity, Mucosal; D007074:Immunoglobulin G / Q000097:blood; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D022283:Herpesvirus Vaccines; D007074:Immunoglobulin G; D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: Correlate of protection; Effector memory T cells; HSV vaccine; HSV1; Mucosal infection; Tat