title: Vaginal protection and immunity after oral immunization of mice with a novel vaccine strain of Listeria monocytogenes expressing human immunodeficiency virus type 1 gag.
abstract: Natural transmission of human immunodeficiency virus (HIV) occurs at mucosal surfaces. During acute infection, intestinal and other mucosae are preferential sites of virus replication and rapidly become depleted of CD4(+) T cells. Therefore, mucosal immunity may be critical to control both initial infection and the massive early spread of virus. An attenuated D-alanine-requiring strain of the oral intracellular microorganism Listeria monocytogenes expressing HIV type 1 gag was shown to induce protective cell-mediated immunity in mice against viruses that express HIV gag when immunization occurs in the presence of a transient supply of D-alanine. In this study, we examined the efficacy of new attenuated strains that are able to synthesize d-alanine from a heterologous dal gene tightly regulated by an actA-promoted resolvase recombination system. In the absence of d-alanine, Gag-specific cytotoxic T lymphocytes (CTLs) were induced systemically after intravenous immunization, and one strain, Lmdd-gag/pARS, induced strong dose-dependent Gag-specific CTLs after oral immunization. A significant level of Gag-specific CD8(+) T cells was induced in the mucosal-associated lymphoid tissues (MALTs). Upon intravaginal challenge of these orally immunized mice with recombinant vaccinia virus (rVV) expressing HIV gag, gamma interferon- and tumor necrosis factor alpha-secreting Gag-specific CD8(+) T cells were dramatically increased in the spleen and MALTs. Oral immunization with Lmdd-gag/pARS led to complete protection against vaginal challenge by a homologous clade B gag-expressing rVV. In addition, strong cross-clade protection was seen against clades A and C and partial protection against clade G gag-expressing rVV. These results suggest that Lmdd-gag/pARS may be considered as a novel vaccine candidate for use against HIV/AIDS.
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, 203C Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104, USA.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Zhao
authors.forename: Manxin
authors.initials: M
authors.lastname: Zhang
authors.forename: Zhongxia
authors.initials: Z
authors.lastname: Li
authors.forename: Fred R
authors.initials: FR
authors.lastname: Frankel
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015683:Gene Products, gag / Q000096:biosynthesis* / Q000235:genetics; D007371:Interferon-gamma / Q000097:blood; D008089:Listeria monocytogenes / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014621:Vagina / Q000821:virology; D014623:Vaginal Diseases / Q000517:prevention & control* / Q000821:virology; D014765:Viral Vaccines / Q000235:genetics*
chemical_list: D015683:Gene Products, gag; D014409:Tumor Necrosis Factor-alpha; D014765:Viral Vaccines; D007371:Interferon-gamma