Transmission of HIV-1 occurs predominately at mucosal surfaces and therefore a successful vaccine against HIV-1 must induce mucosal humoral and cellular immune responses. Lactic acid bacteria have been used for centuries to process and preserve food and are well known for their probiotic activities. Recently members of the lactic acid bacteria family have been explored as vaccine vectors. Lactobacillus gasseri is a common commensal of the human oral cavity and gastrointestinal tract and may be particularly useful as an oral mucosal vaccine vector against HIV-1. L. gasseri colonizes the oral cavity and serves as a source for colonization of the intestinal tract. In addition, L. gasseri activates dendritic cells and stimulates cytokine production that leads to Th1 polarization of T cells. In preliminary studies, recombinant L. gasseri expressing HIV-1 Gag induced serum IgG, mucosal IgA and cell mediated responses measured in the colon and reproductive tract after a single oral dose. Here we propose to better determine the dose, distribution and persistence of L. gasseri after oral immunization. We will then refine L. gasseri as an immunogen by co-expressing flagellin as a means to stimulate the innate immune system through TLR5 and determining whether L. gasseri can deliver a DNA vaccine for the eukaryotic expression of Env. The role of regulatory T cells in mucosal immunization will be assessed by depleting Treg concomitant with oral immunization. Finally, a robust challenge study will be performed to determine whether L. gasseri can induce protective immunity. These studies will be performed using the cat/FIV model of HIV-1 since cats have oropharyngeal mucosa associated lymphoid tissue similar to humans, can be economically studied using statistically relevant numbers, and can be vaginally challenged with pathogenic FIV using cell-associated and cell-free virus. Project Narrative: Transmission of HIV-1 occurs predominately at mucosal surfaces and therefore a successful vaccine against HIV-1 must induce mucosal humoral and cellular immune responses. Lactobacillus gasseri is a common probiotic bacterium found in the human oral cavity and gastrointestinal tract and as such may be a particularly effective vaccine vector against HIV-1. Studies proposed here will investigate strategies to engineer recombinant L. gasseri that can induce a protective immune response against HIV-1 via the oral mucosa.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019069-06
Application #
8208234
Study Section
Special Emphasis Panel (ZDE1-MS (09))
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2008-03-20
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
6
Fiscal Year
2012
Total Cost
$339,531
Indirect Cost
$111,658
Name
Colorado State University-Fort Collins
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Stoeker, Laura L; Overman, Elizabeth L; Nordone, Shila K et al. (2013) Infection with feline immunodeficiency virus alters intestinal epithelial transport and mucosal immune responses to probiotics. Vet Immunol Immunopathol 153:146-52
Stoeker, Laura; Nordone, Shila; Gunderson, Sara et al. (2011) Assessment of Lactobacillus gasseri as a candidate oral vaccine vector. Clin Vaccine Immunol 18:1834-44
Kajikawa, Akinobu; Nordone, Shila K; Zhang, Lin et al. (2011) Dissimilar properties of two recombinant Lactobacillus acidophilus strains displaying Salmonella FliC with different anchoring motifs. Appl Environ Microbiol 77:6587-96