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MZC Gel Inhibits Ex Vivo HIV-1 and HSV-2 Infection in Human Cervical Mucosa
Guillermo Villegas1, Giulia Calenda1, Patrick Barnable1, Keith Levendosky1, Michael Cooney1, José Fernández-Romero1, Thomas Zydowsky1, Natalia Teleshova1
1 Population Council, New York, NY, United States.
The transmission of HIV-1 is increased in the presence of other STIs. Of all ulcerative STIs, HSV-2 most strongly impacts sexual transmission and acquisition of HIV. Microbicide products that protect women against HIV and HSV-2 would make a major contribution to public health globally. The Population Council's leading microbicide gel (MZC) containing 50µM MIV-150 (M), 14mM Zinc acetate and Carrageenan (CG) protects against SHIV-RT infection vaginally for up to 8h and rectally for 1h. This study aimed to test activity of MZC against HIV-1/HSV-2 co-infection in human cervical explants.
Methods: HIV-1BaL stock was prepared in the presence of 10µM retinoic acid and 20U/ml of IL-2 in human PBMCs (RA HIV-1BaL). Non-stimulated human ectocervical explants were challenged with 500 TCID50 RA HIV-1BaL or co-challenged with 500 TCID50 RA HIV-1BaL and 106 pfu HSV-2 per explant for ~18h. The viral challenge was performed in the presence of 1:100 and 1:300 diluted MZC (vs. untreated medium, diluted CG and 3TC/Acyclovir controls). The tissues were washed after the ~18h incubation and cultured for 14d. Infections were monitored by one step HIV gag RT-qPCR and HSV-2 pol qPCR on culture supernatants. SOFT and CUM endpoint analyses were performed. Tissue viability post exposure to diluted gels was tested using MTT assay. Log-normal generalized linear mixed models were used for data analysis.
Results: Tissue challenge with RA HIV-1BaL and HSV-2 resulted in robust infection of non-stimulated tissue with both viruses (single RA HIV-1Bal challenge and co-challenge). MZC (1:100 and 1:300 dilutions) significantly inhibited RA HIV-1BaL infection (vs. medium control) in the single challenge and in the co-challenge models (p<0.0001 and p<0.001, respectively). RA HIV-1BaL infection level decreased in CG treated tissues (vs. medium control) probably due to a barrier effect (only single challenge; p<0.001 for 1:100 dilution only). Both MZC and CG gels (1:100) strongly inhibited HSV-2. The gel formulations did not decrease tissue viability.
Conclusions: MZC is active against RA HIV-1BaL in the single challenge model and under stringent conditions of co-challenge with HSV-2 in human ectocervical mucosa. MZC provides CG-mediated activity against high dose HSV-2 challenge. These results highlight the promise for further development of MZC as a microbicide and support the ongoing Phase 1 testing of vaginal MZC.