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THE ROLE OF EPITHELIAL INTEGRITY AND METABOLIZING ENZYMES IN TOPICAL MICROBICIDE EFFICACY FOR THE PREVENTION OF HIV SEXUAL TRANSMISSION

Hu, Minlu (2016) THE ROLE OF EPITHELIAL INTEGRITY AND METABOLIZING ENZYMES IN TOPICAL MICROBICIDE EFFICACY FOR THE PREVENTION OF HIV SEXUAL TRANSMISSION. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

In order to further reduce the number of HIV-1 infections, efforts must be made to prevent new acquisition of HIV in healthy population. Although the antiretroviral-based topical (microbicides) and oral pre-exposure prophylaxis (PrEP) products have been evaluated in a number of clinical trials, the results from these studies have been inconsistent. The aim of my dissertation study is to examine whether the modulators of tissue integrity and metabolizing enzymes could affect antiretroviral drug exposure and efficacy in cervicovaginal tissues.

First of all, we demonstrated that the several commonly used excipients which increased paracellular permeability of cervicovaginal tissue did not significantly reduce tenofovir (TFV) activity in HIV-1 prevention in an ex vivo explant tissue model. In addition, TEER, morphology, permeability, and MTT-based tissue viability do not necessarily change in parallel with each other and the use of a single measurement cannot accurately reflect the effect of excipients on cervicovaginal tissue integrity. Also, we found that the mRNA of several Phase I and II metabolizing enzyme isoforms, such as CYP1A1, CYP1B1 and UGT1A1, are highly expressed in the human female genital tract. In phosphorylating enzymes study, we found that the majority of TFV-related phosphorylating enzymes showed significantly decreased mRNA level in T cells as compared to their levels in cervicovaginal tissues. Furthermore, our results indicated that medroxyprogesterone acetate and progestone treatments changed the activity of phosphorylating enzymes toward different directions in cervicovaginal epithelial cell line (VK2) and a T cell line (PM1). Additionally, we found that medroxyprogesterone acetate, progestone, IL1β and IL8 treatment resulted in altered tenofovir diphosphate level in a vaginal epithelial cell line and a T cell line. Taken together, these studies provide valuable information on the excipients’ effect on multiple aspects of cervicovaginal tissue integrity, as well as what biological factors may affect the effectiveness of TFV and its clinical potential. Such information will facilitate the efforts toward optimized vaginal PrEP products for HIV-1 prevention.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Hu, Minlumih54@pitt.eduMIH54
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorRohan, Lisa C.lrohan@mwri.magee.edu
Committee ChairPoloyac, Samuel M.poloyac@pitt.edu
Committee MemberDezzutti, Charlene S.cdezzutti@mwri.magee.edu
Committee MemberEmpey, Philip E.pempey@pitt.edu
Committee MemberBeumer, Jan H.jhb11@pitt.edu
Date: 2 August 2016
Date Type: Publication
Defense Date: 24 May 2016
Approval Date: 2 August 2016
Submission Date: 26 July 2016
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 193
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Microbicides, HIV, excipient, tenofovir, Vaginal epithelium, phosphorylating enzymes
Date Deposited: 02 Aug 2016 12:22
Last Modified: 15 Nov 2016 14:34
URI: http://d-scholarship.pitt.edu/id/eprint/28694

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