eprintid: 26422 rev_number: 40 userid: 5293 dir: disk0/00/02/64/22 datestamp: 2016-01-27 22:25:01 lastmod: 2017-01-01 06:15:08 status_changed: 2016-01-27 22:25:01 type: thesis_degree metadata_visibility: show contact_email: yanillescott@yahoo.com item_issues_count: 0 eprint_status: archive creators_name: Scott, Yanille creators_email: yas23@pitt.edu creators_id: YAS23 title: The potential of broadly neutralizing HIV antibodies to function as microbicides ispublished: unpub divisions: sch_gsph_infectiousdiseasesmicrobiology full_text_status: public keywords: HIV microbicides, HIV prevention, neutralizing antibodies abstract: Microbicides are products designed for vaginal or rectal use to prevent transmission of the human immunodeficiency virus (HIV). The first generation non-antiretroviral (non-ARV) microbicide candidates were intended to be a low-cost, female-controlled method of HIV prophylaxis because young women in the poorest regions of the world are disproportionately affected by HIV. However, these early microbicide candidates were not HIV specific and some disrupted the vaginal epithelium, increased immune activation in the female genital tract, or disturbed vaginal flora, while others simply did not work. Due to the poor clinical success of these first-generation candidates, there was a shift in focus to developing antiretroviral (ARV) compounds like tenofovir and dapivirine as microbicides. However, ARV-based microbicides may not prevent transmission of drug-resistant HIV. Moreover, not all persons may want to use an ARV-based product due to the potential of drug side-effects and the risk of developing drug-resistance if the product is used inappropriately. While there has been progress in developing a product for oral HIV pre-exposure prophylaxis (PrEP), there are still no commercially available topical microbicide products. Topical microbicides are desirable because they deliver active agents directly to the vaginal or rectal mucosa where HIV transmission occurs while avoiding systemic drug exposure. Hence non-ARV based microbicides are of great public health significance as a user-controlled tool for reducing the sexual transmission of HIV toward achieving the 2030 Sustainable Development Goal of ending AIDS and ensuring good health and well-being for all. Consequently, several years after the failure of the first generation of non-ARV vaginal gel microbicides, the lessons learned from these early trials have given rise to more rigorous preclinical evaluation protocols and novel formulation and delivery technologies for microbicides. This has resulted in renewed interest and new approaches to developing non-ARV microbicides. The new generation of non-ARV microbicide candidates being developed includes active biologics like broadly neutralizing monoclonal antibodies. This dissertation presents a pre-clinical evaluation of the potential of unformulated monoclonal HIV neutralizing antibodies to function as topical HIV microbicides in vitro and using human ex vivo models of rectal and vaginal mucosal transmission. date: 2016-01-27 date_type: published pages: 107 institution: University of Pittsburgh refereed: TRUE etdcommittee_type: thesis_advisor etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_name: Dezzutti, Charlene S. etdcommittee_name: Martinson, Jeremy J. etdcommittee_name: Sluis-Cremer, Nicolas etdcommittee_name: Reinhart, Todd A. etdcommittee_email: rsicsd@mwri.magee.edu etdcommittee_email: jmartins@pitt.edu etdcommittee_email: nps2@pitt.edu etdcommittee_email: reinhar@pitt.edu etdcommittee_id: CSD13 etdcommittee_id: JMARTINS etdcommittee_id: NPS2 etdcommittee_id: REINHAR etd_defense_date: 2015-12-18 etd_approval_date: 2016-01-27 etd_submission_date: 2015-11-23 etd_release_date: 2016-01-27 etd_access_restriction: 1_year etd_patent_pending: FALSE thesis_type: dissertation degree: PhD citation: Scott, Yanille (2016) The potential of broadly neutralizing HIV antibodies to function as microbicides. Doctoral Dissertation, University of Pittsburgh. (Unpublished) document_url: http://d-scholarship-dev.library.pitt.edu/26422/1/Yanille_Scott-Dissertation_ETD_December_2015.pdf