Project 4 will use the SHIV/female rhesus macaque model to evaluate the toxicity and efficacy of 2 candidate vaginal microbicides, RC-101 and CSIC. Two different SHIVs will be required because RC-101 is HIV-1 env specific and CSIC is HIV-1 RT specific. SHIV162p4 carries the HIV-1 env and RT-SHIV carries the HIV-1 RT coding region. Project 4 will interact closely with the projects 1-3 and the cores that will carry out the in vitro studies needed to validate RC-101 and CSIC for use in the monkey model. There are 5 aims: 1. To assess vaginal and systemic toxicity of CSIC and RC-101 in adult rhesus macaques. Vaginal colposcopy will assess inflammation associated with drugs in the silicone rings that will be specially made for use in macaques. Sera will be tested for absorption of drug(s) and vaginal washes will be used to assess release of drug into the vaginal vault. 2. To determine the minimal infectious dose for RT-SHIV by the vaginal route. Although SHIV162p4 is well characterized for vaginal infection, there are no reports on RT-SHIV infection by a mucosal route. Six macaques will be used to determine the minimal infectious dose of RTSHIV by the vaginal route. 3. To test the efficacy of RC-101 as a vaginal microbicide against SHIV162p4. Twelve female rhesus macaques will be used to test prevention of transmission by vaginal silicone ring application containing RC-101 4. To test the efficacy of CSIC, a non-nucleoside RT inhibitor against vaginal challenge with RT-SHIV. Twelve female rhesus macaques will be used to test prevention of transmission by CSIC containing silicone rings. 5. To test the efficacy of the combination of CSIC and RC-101.The final plan is to deliver both drugs in the same ring formulation. The goal is to show that these 2 drugs can be used together and will afford better protection against HIV-1 vaginal infection than either could alone. All animals will be monitored for infection for 6 months. This is a highly collaborative project that will closely coordinate with all other projects.

Public Health Relevance

Evaluation of toxicity and efficacy of microbicides CSIC and RC101 against challenge virus in monkey model is essential to develop a practical microbicide that will be used for clinical trial in human.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082623-03
Application #
8317576
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$550,389
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Eade, Colleen R; Diaz, Camila; Chen, Sixue et al. (2015) HIV-Enhancing Factors Are Secreted by Reproductive Epithelia upon Inoculation with Bacterial Vaginosis-Associated Bacteria. Protein Pept Lett 22:672-80
Wood, Matthew P; Cole, Amy L; Eade, Colleen R et al. (2014) The HIV-1 gp41 ectodomain is cleaved by matriptase to produce a chemotactic peptide that acts through FPR2. Immunology 142:474-83
Wood, Matthew P; Cole, Amy L; Ruchala, Piotr et al. (2013) A compensatory mutation provides resistance to disparate HIV fusion inhibitor peptides and enhances membrane fusion. PLoS One 8:e55478
Eade, Colleen R; Cole, Amy L; Diaz, Camila et al. (2013) The anti-HIV microbicide candidate RC-101 inhibits pathogenic vaginal bacteria without harming endogenous flora or mucosa. Am J Reprod Immunol 69:150-8
Eade, Colleen R; Diaz, Camila; Wood, Matthew P et al. (2012) Identification and characterization of bacterial vaginosis-associated pathogens using a comprehensive cervical-vaginal epithelial coculture assay. PLoS One 7:e50106
Levinson, Pauline; Choi, Robert Y; Cole, Amy L et al. (2012) HIV-neutralizing activity of cationic polypeptides in cervicovaginal secretions of women in HIV-serodiscordant relationships. PLoS One 7:e31996
Eade, Colleen R; Wood, Matthew P; Cole, Alexander M (2012) Mechanisms and modifications of naturally occurring host defense peptides for anti-HIV microbicide development. Curr HIV Res 10:61-72
Rinehart, Matthew T; Drake, Tyler K; Robles, Francisco E et al. (2011) Time-resolved imaging refractometry of microbicidal films using quantitative phase microscopy. J Biomed Opt 16:120510
Penberthy, W Todd; Chari, Soumya; Cole, Amy L et al. (2011) Retrocyclins and their activity against HIV-1. Cell Mol Life Sci 68:2231-42

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