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The potential of broadly neutralizing HIV antibodies to function as microbicides

Scott, Yanille (2016) The potential of broadly neutralizing HIV antibodies to function as microbicides. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Scott, Yanilleyas23@pitt.eduYAS23
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorDezzutti, Charlene S.rsicsd@mwri.magee.eduCSD13
Committee MemberMartinson, Jeremy J.jmartins@pitt.eduJMARTINS
Committee MemberSluis-Cremer, Nicolasnps2@pitt.eduNPS2
Committee MemberReinhart, Todd A.reinhar@pitt.eduREINHAR
Date: 27 January 2016
Date Type: Publication
Defense Date: 18 December 2015
Approval Date: 27 January 2016
Submission Date: 23 November 2015
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 107
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: HIV microbicides, HIV prevention, neutralizing antibodies
Date Deposited: 27 Jan 2016 22:25
Last Modified: 01 Jan 2017 06:15
URI: http://d-scholarship.pitt.edu/id/eprint/26422

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