We are developing a oral Salmonella typhimurium-based vaccine to elicit mucosal immunity against sexually-transmitted SIV infection in the rhesus monkey. The vector system is designed to express viral gene products at specified locations within the host mucosal immune system. The current project seeks to investigate the adjuvant mechanisms of S. typhimurium for host responses to these co-delivered SIV antigens. Murine and nonhuman primate (rhesus monkey) models are used to evaluate immune responses to recombinant Salmonella expressing SIV gene products and to investigate the mechanisms responsible for the adjuvant effects seen in these bacterial- based vaccines. The essential interplay between murine and primate experimental systems is fundamental to understanding the role that Salmonella adjuvants play in enhancing host immune responses. Our experimental approaches concentrate on three main properties of the Salmonella-based vaccine system that might explain the dramatic effects observed in many oral vaccination experiments. Firstly, we will characterize the tissue distribution and local host immune response to novel, attenuated strains of Salmonella typhimurium. Individual mutant strains vary in their capacity to invade and replicate in organs of the immune system including Peyer's patches, mesenteric lymph nodes and spleen. The particular properties of each attenuated strain will be characterized in detail to understand the nature of the attenuating mutation and its effects on the adjuvant effect for bacterial and co-delivered antigens. Secondly, we will examine the patterns of immunological reactivity to vaccine strains with particular emphasis on the stimulation of cytotoxic T cell subpopulations bearing the gammadelta T-cell receptor for antigen. Our recent studies indicate a significant role for gammadelta T cells in the host immune response to SIV or HIV-infected cells and this same cell population (bearing the Vgamma9/Vdelta2 receptor) recognizes the Salmonella proteins produced in high levels when the bacterium invades host macrophages. We will determine whether responding gammadelta T cells enhance or inhibit host immune responses to bacterial-based vaccines. Lastly, we will evaluate the duration of immunological memory in mice and monkeys vaccinated with recombinant, attenuated Salmonella-based vaccines. Our ultimate goals are to understand the variety of immunological mechanisms that mediate adjuvant effects of Salmonella and to learn how best to manipulate these features in order to achieve effective vaccination against sexually-transmitted HIV-1 infection in man.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI033237-01
Application #
3548047
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Project Start
1992-08-01
Project End
1995-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Steger, K K; Valentine, P J; Heffron, F et al. (1999) Recombinant, attenuated Salmonella typhimurium stimulate lymphoproliferative responses to SIV capsid antigen in rhesus macaques. Vaccine 17:923-32
Coe, C L; Reyes, T M; Pauza, C D et al. (1997) Quinolinic acid and lymphocyte subsets in the intrathecal compartment as biomarkers of SIV infection and simian AIDS. AIDS Res Hum Retroviruses 13:891-7
Steger, K K; Pauza, C D (1997) Immunization of Macaca mulatta with aroA attenuated Salmonella typhimurium expressing the SIVp27 antigen. J Med Primatol 26:44-50
Trivedi, P; Horejsh, D; Hinds, S B et al. (1996) Intrarectal transmission of simian immunodeficiency virus in rhesus macaques: selective amplification and host responses to transient or persistent viremia. J Virol 70:6876-83
Wallace, M; Bartz, S R; Chang, W L et al. (1996) Gamma delta T lymphocyte responses to HIV. Clin Exp Immunol 103:177-84
Bartz, S R; Hohenwalter, E; Hu, M K et al. (1995) Inhibition of human immunodeficiency virus replication by nonimmunosuppressive analogs of cyclosporin A. Proc Natl Acad Sci U S A 92:5381-5
Wallace, M; Malkovsky, M; Carding, S R (1995) Gamma/delta T lymphocytes in viral infections. J Leukoc Biol 58:277-83
Wallace, M; Gan, Y H; Pauza, C D et al. (1994) Antiviral activity of primate gamma delta T lymphocytes isolated by magnetic cell sorting. J Med Primatol 23:131-5
Trivedi, P; Meyer, K K; Streblow, D N et al. (1994) Selective amplification of simian immunodeficiency virus genotypes after intrarectal inoculation of rhesus monkeys. J Virol 68:7649-53
Bartz, S R; Pauza, C D; Ivanyi, J et al. (1994) An Hsp60 related protein is associated with purified HIV and SIV. J Med Primatol 23:151-4

Showing the most recent 10 out of 12 publications