During the last several years we have developed two novel, unconventional vaccine strategies generating powerful mucosal immunity to SIV antigens. The two vaccine strategies are based on human papilloma virus delivering SIV-cDNAs, designated HPV-SIV, and on HEK293-cells secreting immunogenic chaperone-gp96- Ig-SIV-peptide-complexes, designated gp96-lg-SIV. The vaccines are administered by different routes and generate mucosal immune responses by different molecular and cellular mechanisms. Different molecular mechanisms imply activation of different transcriptional and signaling pathways and may generate different degrees of protection against vaginal SIV challenge. Correlating the pathways activated by the two vaccines with immune response to SIV challenge and protection from disease will provide the information how best to combine the two vaccine strategies, if necessary, for effective protection from SIV disease. Hypothesis 1: Mucosal immunity generated by HPV-SIV and gp96-lg SIV activate different molecular and cellular mechanisms which, in turn, differentially activate the various components of mucosal immunity through different transcriptional and signaling pathways. Differential immune responses in the mucosa will translate to different degrees of protection from vaginal challenge with SIV. Hypothesis 2: Combination of HPV-SIV and gp96-lg-SIV vaccination will synergize in generating mucosal immunity by combining the activation of different transcriptional and signaling pathways thereby generating comprehensive mucosal immunity with increased power to resist vaginal SIV challenge. These hypotheses will be tested in the following specific alms: 1. Vaccinate Rhesus macaques with HPV-SIV and with gp96-lg-SIV and determine the immune response, transcriptional profiles and signaling pathways in the vagina, draining lymph nodes and systemically. 2. Challenge naive and vaccinated macaques with SIV by the vaginal route and determine immune response to the virus and viral responses to immunity during the eclipse period prior to viremia. 3. Determine the effectiveness of the two vaccines singly and in combination in SIV protection SIV infection and correlate with mucus barrier function, immune responses, transcriptional and proteomic profiles.

Public Health Relevance

This application will study two innovative SIV vaccines that are known to generate immune responses at mucosal sites including the female genital tract. Vaccine activity in the genital tract will be analyzed by genomic and proteomic analysis in addition to immunological assays and correlated with protection from vaginal SIV challenge. The combination of the two vaccines offers the potential of comprehensive immune activation in the mucosa providing enhanced resistance to SIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI096396-01
Application #
8193660
Study Section
Special Emphasis Panel (ZAI1-LR-A (M2))
Program Officer
Warren, Jon T
Project Start
2011-09-01
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$2,000,000
Indirect Cost
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
McCormack, Ryan M; Lyapichev, Kirill; Olsson, Melissa L et al. (2015) Enteric pathogens deploy cell cycle inhibiting factors to block the bactericidal activity of Perforin-2. Elife 4:
McCormack, Ryan M; de Armas, Lesley R; Shiratsuchi, Motoaki et al. (2015) Perforin-2 is essential for intracellular defense of parenchymal cells and phagocytes against pathogenic bacteria. Elife 4:
Hatfield, Stephen M; Kjaergaard, Jorgen; Lukashev, Dmitriy et al. (2015) Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med 7:277ra30
Selinger, Christian; Strbo, Natasa; Gonzalez, Louis et al. (2014) Multiple low-dose challenges in a rhesus macaque AIDS vaccine trial result in an evolving host response that affects protective outcome. Clin Vaccine Immunol 21:1650-60
Newman, Robert G; Dee, Michael J; Malek, Thomas R et al. (2014) Heat shock protein vaccination and directed IL-2 therapy amplify tumor immunity rapidly following bone marrow transplantation in mice. Blood 123:3045-55
Gonzalez, Louis; Strbo, Natasa; Podack, Eckhard R (2013) Humanized mice: novel model for studying mechanisms of human immune-based therapies. Immunol Res 57:326-34
Fields, K A; McCormack, R; de Armas, L R et al. (2013) Perforin-2 restricts growth of Chlamydia trachomatis in macrophages. Infect Immun 81:3045-54
Schreiber, Taylor H; Wolf, Dietlinde; Bodero, Maria et al. (2012) T cell costimulation by TNFR superfamily (TNFRSF)4 and TNFRSF25 in the context of vaccination. J Immunol 189:3311-8
Xiao, Yanping; Motomura, Seiichi; Deyev, Vadim et al. (2011) TNF superfamily member 13, APRIL, inhibits allergic lung inflammation. Eur J Immunol 41:164-71