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CCR5 antagonists used as topical microbicides modulate CCR5 expression and may potentially compound HIV infection

Laux, Julie (2017) CCR5 antagonists used as topical microbicides modulate CCR5 expression and may potentially compound HIV infection. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

CCR5 antagonists, such as Maraviroc (MVC) and 5P12-RANTES, are being evaluated as HIV preventatives. The advantage of these drugs is that they restrict HIV entry via CCR5 receptor. However, sub-clinical concentrations could paradoxically increase HIV risk by increasing CCR5 expression.

Peripheral blood mononuclear cells (PBMCs) and cervical tissues were cultured with one HIV antiretrovirals (ARVs), Maraviroc (MVC), 5P12-RANTES, dapivirine (DPV), or griffithsin (GRFT). Immune cells isolated from PBMCs/cervical tissue were stained with live/dead stain and monoclonal antibodies. Samples were analyzed using a BD LSRII flow cytometer and FlowJo v. 10.1 software. To determine if suboptimal concentrations of antiretrovirals (ARVs) influence HIV susceptibility, PBMCs/cervical tissue were treated with MVC, 5P12-RANTES, DPV, or GRFT and challenged with HIV-1BaL. Supernatant was collected on days 3, 7, and 11 and then tested for viral p24 by the AlphaLISA.

In PBMCs, 10 nM and 1nM MVC induced significant enhancement of CCR5+ expression levels when compared to DPV or GRFT treated cells, respectively. There were no significant changes in CCR5 MFI or percent positive cells found in the cervical tissue. HIV replication, via p24 production, did not increase for any drug concentration in PBMCs, but 975nM MVC significantly increased p24 expression in cervical tissue.

MVC is an effective therapeutic for HIV-infected persons, but may be problematic for HIV prevention due to its dose and time dependent qualities. Likewise, 5P12-RANTES showed similar trends in CCR5 expression. Topical application of CCR5 antagonists may be effective for only a short period in the genital tract. Conversely, DPV and GRFT did not affect CCR5 expression. The use of CCR5 antagonists for HIV prevention should be reconsidered as other options become available. The public health impact of improving topical HIV drugs could potentially reduce global HIV prevalence and shift toward an HIV-free world.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Laux, JulieJUL85@pitt.eduJUL850000-0002-9817-3852
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorDezzutti, Charlenecdezzutti@mwri.magee.edu
Committee MemberMailliard, Robbierbm19@pitt.edu
Committee MemberRappocciolo, Giovannagiovanna@pitt.edu
Date: 29 June 2017
Date Type: Publication
Defense Date: 20 April 2017
Approval Date: 29 June 2017
Submission Date: 3 April 2017
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 44
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MPH - Master of Public Health
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Human immunodeficiency virus-1, HIV, topical microbicide
Date Deposited: 29 Jun 2017 22:33
Last Modified: 01 May 2018 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/31209

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