The overall objective of this proposal is to characterize the immune system of the human male genital tract and to explore immunization routes and forms of antigens that are effective in the induction of humoral and cellular immune responses. Because systemic immunizations is usually ineffective at inducing specific immune responses in mucosal tissues and secretions, novel strategies have to be developed to generate protective responses to HIV at the most frequent site of entry. The purpose of the proposed studies is to determine the origin and properties of antibodies in male genital tract secretions, determine whether the mucosal component of the male genital tract belongs to the common mucosal immune system, and evaluate the efficacy of various mucosal and systemic immunization routes and antigen delivery systems that induce humoral and cellular immune responses in the human male genital tract. To achieve these goals, molecular properties of mucosal antibodies in the male genital tract secretions (pre-ejaculate and semen) will be characterize with respect to the antibodies in the male genital tract secretions (pre-ejaculate and semen) will be characterized with respect to the isotype, characteristics of IgA (proportions of monomeric, polymeric, and secretory IgA), the specificity of naturally occurring antibodies to environmental microbial and food antigens (as compared to other external secretions and serum), and properties and specificity of antibodies and cytotoxic T lymphocytes induced by mucosal (nasal, oral, and rectal) and systemic routes of immunization with microbial vaccines. In the selection of suitable antigens for human administration, live and inactivated commercially available poliovirus and influenza virus vaccines and live Salmonella typhi Ty21A vaccine were considered as prototype antigens and vectors that are relevant to the vaccine delivery systems for HIV antigens. In addition, recombinant cholera toxin B subunit, a potent mucosal antigen and adjuvant, will be used for oral and possibly intranasal immunization (and combination of routes) and the ensuing humoral and cellular responses in peripheral blood and external secretions will be evaluated. The properties of antibodies induced in the systemic and mucosal compartments will be determined with respect to the isotype, magnitude, and duration after different routes of administration of live and inactivated vaccines. The accumulated information will provide a rational basis for effective and practical immunization protocols that are effective in generation of immune responses against genitally acquired HIV infection.

Project Start
1999-05-01
Project End
2000-04-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
11
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Mestecky, Jiri; Wright, Peter F; Lopalco, Lucia et al. (2011) Scarcity or absence of humoral immune responses in the plasma and cervicovaginal lavage fluids of heavily HIV-1-exposed but persistently seronegative women. AIDS Res Hum Retroviruses 27:469-86
Wahl, Sharon M; Redford, Maryann; Christensen, Shawna et al. (2011) Systemic and mucosal differences in HIV burden, immune, and therapeutic responses. J Acquir Immune Defic Syndr 56:401-11
Raska, Milan; Takahashi, Kazuo; Czernekova, Lydie et al. (2010) Glycosylation patterns of HIV-1 gp120 depend on the type of expressing cells and affect antibody recognition. J Biol Chem 285:20860-9
Quan, Fu-Shi; Sailaja, Gangadhara; Skountzou, Ioanna et al. (2007) Immunogenicity of virus-like particles containing modified human immunodeficiency virus envelope proteins. Vaccine 25:3841-50
Reeves, R Keith; Fultz, Patricia N (2007) Disparate effects of acute and chronic infection with SIVmac239 or SHIV-89.6P on macaque plasmacytoid dendritic cells. Virology 365:356-68
Wang, Bao-Zhong; Liu, Weimin; Kang, Sang-Moo et al. (2007) Incorporation of high levels of chimeric human immunodeficiency virus envelope glycoproteins into virus-like particles. J Virol 81:10869-78
Liao, Hua-Xin; Sutherland, Laura L; Xia, Shi-Mao et al. (2006) A group M consensus envelope glycoprotein induces antibodies that neutralize subsets of subtype B and C HIV-1 primary viruses. Virology 353:268-82
Gao, Feng; Korber, Bette T; Weaver, Eric et al. (2004) Centralized immunogens as a vaccine strategy to overcome HIV-1 diversity. Expert Rev Vaccines 3:S161-8
Fultz, Patricia N; Stallworth, Jackie; Porter, Donna et al. (2003) Immunogenicity in pig-tailed macaques of poliovirus replicons expressing HIV-1 and SIV antigens and protection against SHIV-89.6P disease. Virology 315:425-37