WASHINGTON STATE CONVENTION CENTER

Seattle, Washington
March 4–7, 2019

 

Conference Dates and Location: 
February 22–25, 2016 | Boston, Massachusetts
Abstract Number: 
876

CVLs From Women Vaginally Dosed With PC-1005 Inhibit Mucosal HIV-1 and HSV-2 Ex Vivo

Author(s): 

Guillermo Villegas1; Shimin Zhang1; Olga Mizenina1; Kyle Kleinbeck1; Michael Cooney1; Craig Hoesley2; George Creasy1; José Fernández-Romero1; Thomas Zydowsky1; Natalia Teleshova1
1Pop Council, New York, NY, USA;2Univ of Alabama at Birmingham, Birmingham, AL, USA

Abstract Body: 

A recent Phase 1 trial demonstrated that PC-1005 gel containing 50µM MIV-150, 14mM zinc acetate dihydrate and carrageenan (CG) applied daily vaginally for up to 14 days is safe and well tolerated. Additionally, cervico-vaginal lavage samples (CVLs) collected 4h or 24h after last gel application showed MIV-150 and CG dose-dependent inhibition of HIV-1 and HPV in cell-based assays (Friedland et al, in preparation). We aimed to determine anti-HIV and anti-HSV-2 activity of CVLs in human ectocervical explants ex vivo.

CVLs collected at the baseline and 4h (n=6 PC-1005 and n=2 hydroxycellulose (HEC) placebo) or 24h (n=6 PC-1005 and n=1 HEC placebo) post last vaginal gel administration during Phase 1 trial were utilized. CG and MIV-150 concentrations in CVLs were measured by ELISA and LC-MS/MS, respectively. Human ectocervical explants were prepared from tissues received from National Disease Research Interchange. Explants (n=3 per condition) were incubated with CVLs (1:1) for 4h, washed with PBS and then challenged with 500 TCID50 HIV-1BaL or co-challenged with 500 TCID50 HIV-1BaL and 106 pfu HSV-2 per explant for ~18h, washed and then cultured for 14d. The activity of each baseline and corresponding post-gel exposure CVL was tested in tissues from the same donor. To determine contribution of CG to anti-HIV activity of CVLs, tissues were challenged with HIV-1Bal after exposure to baseline CVLs spiked with CG concentrations detected in the study (n=3 experiments). Infections were monitored by one step HIV gag RT-qPCR and HSV-2 pol qPCR on culture supernatants (individual replicate analysis). SOFT and CUM endpoint analyses were performed. Tissue viability post exposure to CVLs was tested using MTT assay. Log-normal generalized linear mixed models were used for statistical analysis.   

MIV-150 and CG in CVLs inhibited HIV and HSV-2 infection (single HIV challenge or co-challenge with HSV-2) in the explants in a dose-dependent manner (p≤0.01), with stronger inhibition using CVLs collected 4h post last gel administration. CG concentrations (>250 µg/ml; n=4 CVLs) could have contributed to the observed anti-HIV activity based on >55% HIV-1Bal infection inhibition in the CG spiking experiments.

The anti-HIV and anti-HSV-2 activity of CVLs in human ectocervical explants warrants the further development of PC-1005 gel as a broad-spectrum on demand microbicide.

Session Number: 
P-V2
Session Title: 
Topical and Systemic Preexposure Prophylaxis: New Agents, New Populations
Presenting Author: 
Guillermo Villegas
Presenter Institution: 
Population Council
Poster: