The long term goals of these studies are 1. to develop clinically relevant models for evaluation of intravaginal microbicides using currently available microbicidal compounds; and 2. to assess the utility of naturally-occurring microbicidal systems as vaginal microbicides. The intent is to provide new information which could lead to the development of female-controlled methods for prevention of sexual transmission of STDs/HlV. The studies proposed in this application will evaluate known microbicides (nonoxynol-9, benzalkonium chloride, chlorhexidine) and novel naturally- occurring microbicides in four model systems: 1. in vitro; 2. in raft (organotypic cultures); 3. a primate model; and 4. HIV+ and HIV- women. The spectrum of STD agents to be evaluated include HIV (human model); HPV and HSV 2 (organotypic model); C. trachomatis (in vitro, organotypic model and monkey model); N. gonorrhoeae (in vitro); and T. vaginalis (in vitro). In addition, the effect of these microbicidal agents on the normal vaginal flora including lactobacilli will be evaluated in vitro, in the primate model and in humans. Similarly, tissue toxicity of microbicidal compounds will be evaluated in both primate and Phase l human studies. This multidisciplinary approach will yield new information on currently available microbicidal compounds, lead to development of model systems for evaluation of new microbicides and will assess the potential use of naturally-occurring antimicrobial systems as vaginal microbicides. In project 1, a primate model will be used to evaluate the early stages of infection of C. trachomatis, the effect of available microbicides on the vaginal and cervical epithelium and the effect of these microbicides on chlamydial infection. In project 2, organotypic cultures will be used to evaluate the effect of microbicides on cell phenotype, viability, growth and differentiation, as well as the effects of these compounds on viral gene expression using HPV and HSV-2 gene constructs. In project 3, the lactobacillus-peroxidase-halide antimicrobial system will be evaluated in the vagina of HIV+ and HlV-women, and the effects of exogenous suppositories (containing lactobacillus, recombinant myeloperoxidase, or a combination of both) on C. trachomatis infection and recovery of HIV will be evaluated. In project 4, antimicrobial lipid mixtures which are known to inactivate enveloped viruses (HIV and HSV) will be evaluated for their potential effectiveness as vaginal microbicides. These projects will be supported by an administrative/ epidemiology core, and three scientific cores. A bacteriology/ parasitology core will provide vaginal cultures for projects 1 and 3, and will perform in vitro testing of known microbicides. The chlamydia core will provide purified C. trachomatis for project 1 infection studies, cultures and DNA~amplification methods for use in project 1 and 3, as well as comparing MIC results using standard methods and organotypic model systems. The clinical core will provide tissue for project 2, human subjects for projects 3 and 4, and will investigate the effects of microbicides on HIV recovery from the vagina and cervix. The development and use of effective vaginal microbicides should decrease the sexual transmission of HIV, as well as other STDs that not only facilitate the spread of HIV, but also cause long term health care problems in millions of women each year The proposed studies will yield new information and tools that have immediate applicability to the development of vaginal microbicides.
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