title: In Vitro Exposure to PC-1005 and Cervicovaginal Lavage Fluid from Women Vaginally Administered PC-1005 Inhibits HIV-1 and HSV-2 Infection in Human Cervical Mucosa.
abstract: Our recent phase 1 trial demonstrated that PC-1005 gel containing 50 μM MIV-150, 14 mM zinc acetate dihydrate, and carrageenan (CG) applied daily vaginally for 14 days is safe and well tolerated. Importantly, cervicovaginal lavage fluid samples (CVLs) collected 4 or 24 h after the last gel application inhibited HIV-1 and human papillomavirus (HPV) in cell-based assays in a dose-dependent manner (MIV-150 for HIV-1 and CG for HPV). Herein we aimed to determine the anti-HIV and anti-herpes simplex virus 2 (anti-HSV-2) activity of PC-1005 in human cervical explants after in vitro exposure to the gel and to CVLs from participants in the phase 1 trial. Single HIV-1BaL infection and HIV-1BaL-HSV-2 coinfection explant models were utilized. Coinfection with HSV-2 enhanced tissue HIV-1BaL infection. In vitro exposure to PC-1005 protected cervical mucosa against HIV-1BaL (up to a 1:300 dilution) in single-challenge and cochallenge models. CG gel (PC-525) provided some barrier effect against HIV-1BaL at the 1:100 dilution in a single-challenge model but not in the cochallenge model. Both PC-1005 and PC-525 at the 1:100 dilution inhibited HSV-2 infection, pointing to a CG-mediated protection. MIV-150 and CG in CVLs inhibited HIV (single-challenge or cochallenge models) and HSV-2 infections in explants in a dose-dependent manner (P < 0.05). Stronger inhibition of HIV-1 infection by CVLs collected 4 h after the last gel administration was observed compared to infection detected in the presence of baseline CVLs. The anti-HIV and anti-HSV-2 activity of PC-1005 gel in vitro and CVLs in human ectocervical explants supports the further development of PC-1005 gel as a broad-spectrum on-demand microbicide.
authors.affiliation: Population Council, New York, New York, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Villegas
authors.affiliation: Population Council, New York, New York, USA.
authors.forename: Giulia
authors.initials: G
authors.lastname: Calenda
authors.affiliation: Population Council, New York, New York, USA.
authors.forename: Shimin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Population Council, New York, New York, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Mizenina
authors.affiliation: Population Council, New York, New York, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Kleinbeck
authors.affiliation: Population Council, New York, New York, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cooney
authors.affiliation: University of Alabama Birmingham School of Medicine, Birmingham, Alabama, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Hoesley
authors.affiliation: Population Council, New York, New York, USA.
authors.forename: George W
authors.initials: GW
authors.lastname: Creasy
authors.affiliation: Population Council, New York, New York, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Friedland
authors.affiliation: Population Council, New York, New York, USA.
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández-Romero
authors.affiliation: Population Council, New York, New York, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Zydowsky
authors.affiliation: Population Council, New York, New York, USA nteleshova@popcouncil.org.
authors.forename: Natalia
authors.initials: N
authors.lastname: Teleshova
mesh_terms: D000282:Administration, Intravaginal; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001826:Body Fluids / Q000187:drug effects / Q000821:virology*; D060085:Coinfection / Q000188:drug therapy / Q000821:virology; D005260:Female; D005782:Gels / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006558:Herpes Genitalis / Q000188:drug therapy* / Q000821:virology; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D009092:Mucous Membrane / Q000187:drug effects / Q000821:virology*; D011725:Pyridines / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D014621:Vagina / Q000187:drug effects* / Q000821:virology; D019345:Zinc Acetate / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D005782:Gels; C510296:MIV 150; D011725:Pyridines; D014508:Urea; D054303:HIV Reverse Transcriptase; D019345:Zinc Acetate