title: A combination microbicide gel protects macaques against vaginal simian human immunodeficiency virus-reverse transcriptase infection, but only partially reduces herpes simplex virus-2 infection after a single high-dose cochallenge.
abstract: Herpes simplex virus-2 (HSV-2) infection increases HIV susceptibility. We previously established a rhesus macaque model of vaginal HSV-2 preexposure followed by cochallenge with HSV-2 and simian/human immunodeficiency virus-reverse transcriptase (SHIV-RT). Using this model, we showed that a gel containing the nonnucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 in carrageenan (CG) reduced SHIV-RT infection. To evaluate the efficacy of new generation microbicides against both viruses, we first established dual infection after single vaginal cochallenge with SHIV-RT and HSV-2 in HSV-2-naive macaques. All animals (6/6) became HSV-2 infected, with 4/6 coinfected with SHIV-RT. In a control group cochallenged with SHIV-RT and UV-inactivated HSV-2, 2/4 became SHIV-RT infected, and none had detectable HSV-2. Low-level HSV-2-specific antibody and T cell responses were detected in some HSV-2-infected animals. To test a CG gel containing MIV-150 and zinc acetate (MZC), which provided naive animals full protection from SHIV-RT for at least 8 h, MZC (vs. CG) was applied daily for 14 days followed by cochallenge 8 h later. MZC prevented SHIV-RT infection (0/9 infected, p=0.04 vs. 3/6 in CG controls), but only reduced HSV-2 infection by 20% (6/9 infected vs. 5/6 in CG, p=0.6). In HSV-2-infected animals, none of the gel-treated animals seroconverted, and only the CG controls had measurable HSV-2-specific T cell responses. This study shows the promise of MZC to prevent immunodeficiency virus infection (even in the presence of HSV-2) and reduce HSV-2 infection after exposure to a high-dose inoculum. Additionally, it demonstrates the potential of a macaque coinfection model to evaluate broad-spectrum microbicides.
authors.affiliation: 1 Center for Biomedical Research , Population Council, New York, New York.
authors.forename: Mayla
authors.initials: M
authors.lastname: Hsu
authors.forename: Meropi
authors.initials: M
authors.lastname: Aravantinou
authors.forename: Radhika
authors.initials: R
authors.lastname: Menon
authors.forename: Samantha
authors.initials: S
authors.lastname: Seidor
authors.forename: Daniel
authors.initials: D
authors.lastname: Goldman
authors.forename: Jessica
authors.initials: J
authors.lastname: Kenney
authors.forename: Nina
authors.initials: N
authors.lastname: Derby
authors.forename: Agegnehu
authors.initials: A
authors.lastname: Gettie
authors.forename: James
authors.initials: J
authors.lastname: Blanchard
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.forename: Jose A
authors.initials: JA
authors.lastname: Fernández-Romero
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Zydowsky
authors.forename: Melissa
authors.initials: M
authors.lastname: Robbiani
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage*; D018890:Chemoprevention / Q000379:methods*; D005260:Female; D054303:HIV Reverse Transcriptase; D006558:Herpes Genitalis / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000187:drug effects*; D008253:Macaca mulatta; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage*
chemical_list: D000890:Anti-Infective Agents; D014622:Vaginal Creams, Foams, and Jellies; D054303:HIV Reverse Transcriptase