A better understanding of the mucosal entry oaths used by STD pathogens will aid in designing topical microbicides since these agents must block transmission at mucosal surfaces. This project will study pathways, vectors, and sites of potential high transmission susceptibility. Cell vectoring: Semen contains both free virions, and virus-infected leukocytes that may act as vectors mediating transmission of HIV and other STDs. Leukocytes deposited in the vaginas of mice enter the vaginal epithelium and migrate to regional lymph nodes within a few hours. With experiments in mice, and a in vitro system, we will study relevant determinants of cell entry. Using a newly developed model of vaginal transmission by HIV-infected-cells to hu-PBL-SCID mice, we will correlate details of cell entry with efficiency transmission by HIV- infected-cells to hu-PBL-SCID mice, we will correlate details of cell entry with efficiency of infection. With in vivo studies, we will test if male leukocytes enter female cervicovaginal epithelia. Epithelial microtrauma opens a significant pathway for STD/HIV transmission. We will study the frequency and extent of microtrauma under various circumstances in consensual human coitus, and test factors that may prevent or exacerbate it. These results will be compared with the increase in susceptibility caused by comparable trauma in the mouse HSV-2 and HIV/SCID models. Upper tract exposure: Uterine contractions are now known to transport fluids from the vagina to the upper genital tract, a route whereby pathogens and infected-cells may reach epithelia more susceptible than vaginal epithelium. Using sonography we will study this uterine uptake of vaginal fluids, focusing on variation in uptake associated with menstrual cycle, fluid viscosity, and the effect of semen and semen constituents. We will attempt to block uterine uptake (and exposure) using mucus- thickening lubricants, by interposing cervical barriers, and by pharmacologic means. Effective distribution of topical microbicides is critical for their effectiveness since they can only protect those surface to which they have been adequately delivered. Antibody-based microbicides offer unique potential for genital distribution that may extend from the upper tract to vulva, particularly after repeated non-coital dosing. We will study the extent of distribution of vaginally applied human antibodies in women, in experiments that will coordinate with the Specific Aims of Projects 2 and 3.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI045967-02
Application #
6345950
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2000-09-01
Project End
2001-08-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
$266,487
Indirect Cost
Name
Johns Hopkins University
Department
Type
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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