Our broad long-term objective is to prevent sexual transmission of HIV by changing the genital tract milieu to one that decreases the risk of HIV infection. Since a major route of HIV transmission is between heterosexual partners, a promising HIV-prevention approach is to topically modify the microbiology and immunology of the female genital tract. Using our recently published cervical explant model, we intent to investigate the role of cervical secretion (CVL)s in determining the susceptibility to HIV-1 infection. Our laboratory is particularly well- qualified to investigate key HIV-1 related modifications in the immunology and virology of the female genital tract including susceptibility to HIV infection and expression on HIV-receptors such as chemokine receptors (CheRec) and CDR. Our hypothesis is: HIV-1 susceptibility is altered by the microbiology/immunology of the female genital tract through the production of factors in cervical secretion (CVL)s that either inhibit or stimulate HIV-1 production. In the following AIMS, we propose 4 questions corresponding to 2 different intentionally in explant culture. [1a] Does the addition of lysates from cultures of organisms known to cause bacterial vaginosis (see subproject 0001, a condition associated with increased risk of HIV-1 transmission, to cut our cervical explant model increase or decrease susceptibility to different isolates of HIV-1? [1b] Does the addition of cervical [CVL)s from women in our cohorts with cultured confirmed bacterial vaginosis to our cervical explant model increase or decrease susceptibility to different isolates of HIV-1? [2a] Does the addition of IgA or IgG from cervical secretions (CVL)s of HIV-1 exposed-uninfected women (see subproject 0002) to our cervical explant model increase or decrease susceptibility to different isolates of HIV-1? (2b) Does the addition of cervical secretion (CVLs)s (i.e. IgA), known to inhibit HIV-1 in vitro, from HIV-1, exposed-uninfected women (see subproject 0001) to our cervical explant model increase or decrease susceptibility to different isolates of HIV-1? Confirmation of our hypotheses of our hypotheses through these specific aims may result in successful HIV-1 prevention strategies applicable to women in developing nations.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD040539-01
Application #
6467544
Study Section
Special Emphasis Panel (ZHD1)
Project Start
2001-04-23
Project End
2006-03-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Spear, Gregory T; Kendrick, Sabrina R; Chen, Hua Y et al. (2011) Multiplex immunoassay of lower genital tract mucosal fluid from women attending an urban STD clinic shows broadly increased IL1ß and lactoferrin. PLoS One 6:e19560
Cook, Judith A (2011) Associations between use of crack cocaine and HIV-1 disease progression: research findings and implications for mother-to-infant transmission. Life Sci 88:931-9
St John, Elizabeth P; Zariffard, M Reza; Martinson, Jeffrey A et al. (2009) Effect of mucosal fluid from women with bacterial vaginosis on HIV trans-infection mediated by dendritic cells. Virology 385:22-7
Anzinger, Joshua J; Olinger, Gene G; Spear, Gregory T (2008) Donor variability in HIV binding to peripheral blood mononuclear cells. Virol J 5:95
Spear, Gregory T; Sikaroodi, Masoumeh; Zariffard, M Reza et al. (2008) Comparison of the diversity of the vaginal microbiota in HIV-infected and HIV-uninfected women with or without bacterial vaginosis. J Infect Dis 198:1131-40
Spear, Gregory T; Zariffard, M Reza; Cohen, Mardge H et al. (2008) Vaginal IL-8 levels are positively associated with Candida albicans and inversely with lactobacilli in HIV-infected women. J Reprod Immunol 78:76-9
Mares, Debra; Simoes, Jose A; Novak, Richard M et al. (2008) TLR2-mediated cell stimulation in bacterial vaginosis. J Reprod Immunol 77:91-9
Novak, Richard M; Donoval, Betty A; Graham, Parrie J et al. (2007) Cervicovaginal levels of lactoferrin, secretory leukocyte protease inhibitor, and RANTES and the effects of coexisting vaginoses in human immunodeficiency virus (HIV)-seronegative women with a high risk of heterosexual acquisition of HIV infection. Clin Vaccine Immunol 14:1102-7
St John, Elizabeth P; Martinson, Jeff; Simoes, Jose A et al. (2007) Dendritic cell activation and maturation induced by mucosal fluid from women with bacterial vaginosis. Clin Immunol 125:95-102
Fox-Canale, Andrea M; Hope, Thomas J; Martinson, Jeffrey et al. (2007) Human cytomegalovirus and human immunodeficiency virus type-1 co-infection in human cervical tissue. Virology 369:55-68

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