title: Short communication: a repeated simian human immunodeficiency virus reverse transcriptase/herpes simplex virus type 2 cochallenge macaque model for the evaluation of microbicides.
abstract: Epidemiological studies suggest that prevalent herpes simplex virus type 2 (HSV-2) infection increases the risk of HIV acquisition, underscoring the need to develop coinfection models to evaluate promising prevention strategies. We previously established a single high-dose vaginal coinfection model of simian human immunodeficiency virus (SHIV)/HSV-2 in Depo-Provera (DP)-treated macaques. However, this model does not appropriately mimic women's exposure. Repeated limiting dose SHIV challenge models are now used routinely to test prevention strategies, yet, at present, there are no reports of a repeated limiting dose cochallenge model in which to evaluate products targeting HIV and HSV-2. Herein, we show that 20 weekly cochallenges with 2-50 TCID50 simian human immunodeficiency virus reverse transcriptase (SHIV-RT) and 10(7) pfu HSV-2 results in infection with both viruses (4/6 SHIV-RT, 6/6 HSV-2). The frequency and level of vaginal HSV-2 shedding were significantly greater in the repeated exposure model compared to the single high-dose model (p<0.0001). We used this new model to test the Council's on-demand microbicide gel, MZC, which is active against SHIV-RT in DP-treated macaques and HSV-2 and human papillomavirus (HPV) in mice. While MZC reduced SHIV and HSV-2 infections in our repeated limiting dose model when cochallenging 8 h after each gel application, a barrier effect of carrageenan (CG) that was not seen in DP-treated animals precluded evaluation of the significance of the antiviral activity of MZC. Both MZC and CG significantly (p<0.0001) reduced the frequency and level of vaginal HSV-2 shedding compared to no gel treatment. This validates the use of this repeated limiting dose cochallenge model for testing products targeting HIV and HSV-2.
authors.affiliation: 1 Population Council , New York, New York.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kenney
authors.forename: Nina
authors.initials: N
authors.lastname: Derby
authors.forename: Meropi
authors.initials: M
authors.lastname: Aravantinou
authors.forename: Kyle
authors.initials: K
authors.lastname: Kleinbeck
authors.forename: Ines
authors.initials: I
authors.lastname: Frank
authors.forename: Agegnehu
authors.initials: A
authors.lastname: Gettie
authors.forename: Brooke
authors.initials: B
authors.lastname: Grasperge
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: 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*; D060085:Coinfection / Q000821:virology*; D003271:Contraceptive Agents, Female / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D006558:Herpes Genitalis / Q000150:complications / Q000821:virology*; D018258:Herpesvirus 2, Human / Q000254:growth & development*; D008253:Macaca mulatta; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000201:enzymology / Q000254:growth & development*; D016896:Treatment Outcome; D014621:Vagina / Q000821:virology; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage; D017201:Virus Shedding
chemical_list: D000890:Anti-Infective Agents; D003271:Contraceptive Agents, Female; D014622:Vaginal Creams, Foams, and Jellies; D017258:Medroxyprogesterone Acetate; D054303:HIV Reverse Transcriptase