IDM Master's Defense

Julie Laux - MPH-PEL Defense

Thursday 4/20 8:30AM - 9:30AM
Conference Room 2140 Parran Hall

"CCR5 Antagonists Used as

Topical Microbicides Modulate CCR5 Expression

and May Compound HIV Infection"

Abstract:  CCR5 antagonists, such as Maraviroc (MVC) and 5P12-RANTES, are being evaluated as HIV preventatives. Their advantage is 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 tissue were cultured with one HIV antiretrovirals (ARVs), Maraviroco (MVC), 5P12-RANTES, dapivirine (DPV), or griffithsin (GRFT).  PBMCs/cervical tissue’s isolated immune cells 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 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 then tested for viral p24 by the AlphaLISA.

10 nM and 1nM MVC induced greater CCR5+ expression when compared to DPV or GRFT treated cells, respectively. No drug concentrations had a significant increase in percent positive CCR5+CD4+ cells. 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 therapeutics 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 would reduce global HIV prevalence and shift toward an HIV-free world.

Last Updated On Friday, April 07, 2017 by Malenka, Judith Ann
Created On Friday, April 07, 2017