This Program Project will study entry paths used by STD pathogens, develop and test human monoclonal antibodies as microbicides for blocking pathogen entry, and characterize how antibodies are deployed and function in preventing infectious entry of pathogens in the female reproductive tract. Project 1. Mucosal entry paths used by STD pathogens will investigate entry paths that topical microbicides must blocks: (a) Cell vectors, such as HIV-infected leukocytes, may penetrate genital epithelial and carry HIV directly to target cells in the lymph nodes. (b) Microtrauma that occurs during consensual intercourse, increasing the risk that pathogens will contact target cells. (c) Upper tract exposure. Uterine peristalis causes uptake of vaginal fluids that may expose the upper reproductive tract to STD pathogens. Project 2. Blocking STD pathogen entry with mucosal antibodies will develop monoclonal human antibodies as highly potent and specific microbicides. Pharmacokinetics of a """"""""plantibody"""""""" against HSV-2 (a human monoclonal produced in corn for large scale, inexpensive production) will be determined in mouse and rabbit vaginas. New human monoclonals will be developed against HPV, and against leukocyte cell vectors for HIV. Protective efficacy will be tested in vitro and in SCID mouse models. Using mouse monoclonals to identify adhesins and host receptors, human monoclonals against chlamydia and gonorrhea will be generated and tested in mice. Monoclonals will also be tested for their ability to markedly reduce a commensal bacterium in the mouse vagina. Project 3. Uptake of Ig by vaginal epithelial cells will investigate how cervico-vaginal epithelial cells (in tissue culture and in vivo_ deploy Ig in the vaginal epithelium, and the effects of physiological modulators (hormones, cytokines) on Ig uptake, storage and release. Human monoclonals identified in Project 2 will be applied to explants of human genital tissues and immortalized epithelial cell lines, to determine whether monoclonals that have been taken up by epithelial cells are effective for blocking HIV, HSV-2, and chlamydia infections, and for blocking adhesions and transepithelial migration of leukocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
3P01AI045967-01S1
Application #
6312474
Study Section
Special Emphasis Panel (ZAI1 (M4))
Program Officer
Savarese, Barbara M
Project Start
1999-09-30
Project End
2003-08-31
Budget Start
1999-09-30
Budget End
2000-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$23,208
Indirect Cost
Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
O'Hanlon, Deirdre E; Moench, Thomas R; Cone, Richard A (2013) Vaginal pH and microbicidal lactic acid when lactobacilli dominate the microbiota. PLoS One 8:e80074
O'Hanlon, Deirdre E; Moench, Thomas R; Cone, Richard A (2011) In vaginal fluid, bacteria associated with bacterial vaginosis can be suppressed with lactic acid but not hydrogen peroxide. BMC Infect Dis 11:200
O'Hanlon, Deirdre E; Lanier, Blair R; Moench, Thomas R et al. (2010) Cervicovaginal fluid and semen block the microbicidal activity of hydrogen peroxide produced by vaginal lactobacilli. BMC Infect Dis 10:120
Chancey, Caren J; Khanna, Kristen V; Seegers, Jos F M L et al. (2006) Lactobacilli-expressed single-chain variable fragment (scFv) specific for intercellular adhesion molecule 1 (ICAM-1) blocks cell-associated HIV-1 transmission across a cervical epithelial monolayer. J Immunol 176:5627-36
Cone, Richard A; Hoen, Timothy; Wong, Xixi et al. (2006) Vaginal microbicides: detecting toxicities in vivo that paradoxically increase pathogen transmission. BMC Infect Dis 6:90
Tien, Deborah; Schnaare, Roger L; Kang, Feirong et al. (2005) In vitro and in vivo characterization of a potential universal placebo designed for use in vaginal microbicide clinical trials. AIDS Res Hum Retroviruses 21:845-53
Olmsted, Stuart S; Khanna, Kristen V; Ng, Erina M et al. (2005) Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model. BMC Infect Dis 5:79
Spencer, Steven E; Valentin-Bon, Iris E; Whaley, Kevin et al. (2004) Inhibition of Neisseria gonorrhoeae genital tract infection by leading-candidate topical microbicides in a mouse model. J Infect Dis 189:410-9
Moench, Thomas; Mehrazar, Karim; Cone, Richard et al. (2004) Sensitive methods to detect epithelial disruption: tests for microhemorrhage in cervicovaginal lavages. J Acquir Immune Defic Syndr 37 Suppl 3:S194-200
Boskey, Elizabeth R; Moench, Thomas R; Hees, Paul S et al. (2003) A self-sampling method to obtain large volumes of undiluted cervicovaginal secretions. Sex Transm Dis 30:107-9

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