The long-term objective of Core C is to assess the in vitro efficacy and toxicity of Cyanovirin (generated by Lactobacilli) as well as the naturally occurring antimicrobial peptide, Retrocyclin. By providing a natural route of delivery for the microbicides and maintaining the acidic environment of the vagina, these microbicides offer a unique approach to HIV prevention. The proposed in vitro testing algorithm will aid in advancing safe, novel microbicide combination strategies from preclinical to clinical studies. Formulations of each microbicide will be tested in the individual laboratories for Project 1 (Cyanovirin) and Project 2 (Retrocyclin), and only those with the highest anti-HIV activity will be sent to Core C for testing. It is anticipated that one to two compounds per year from each project will be tested in the following in vitro algorithm: 1) Microbicides from Projects 1 and 2 will initially be tested in a CD4-dependent, cell-cell transmission assay to assess the ability of these compounds to inhibit cell to cell infection with a CCR5-tropic HIV-1 strain (JR-CSF molecular clone). 2) If positive activity is observed in this assay, testing of each active compound will be repeated in this assay in the presence of mucin or a pH transition. This secondary testing will help determine if interaction of the compound with mucin or an acidic environment, similar to what may occur in the vagina, might affect the ability of the microbicide to inihibit cell to cell HIV-1 transmission. 3) If positive activity is observed in the repeat testing, each active compound will be tested in a CD4-dependent, cell-cell transmission assay that utilizes a CXCR4-tropic HIV-1 strain (SK-1 clinical isolate); however, further testing with mucin or a pH transition will not be done for this assay. 4) In parallel to steps 1-3 of the algorithm, all compounds sent to this Core will be tested for toxicity by assessing their effect on L. crispatus and L. jensenii growth and determining those concentrations that inhibit bacterial growth. These data, in conjunction with tissue explant and animal studies, will help determine the best candidates for clinical trials.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZRG1)
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University of Pittsburgh
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Gupta, Phalguni; Lackman-Smith, Carol; Snyder, Beth et al. (2013) Antiviral activity of retrocyclin RC-101, a candidate microbicide against cell-associated HIV-1. AIDS Res Hum Retroviruses 29:391-6
Gupta, Phalguni; Ratner, Deena; Ding, Ming et al. (2012) Retrocyclin RC-101 blocks HIV-1 transmission across cervical mucosa in an organ culture. J Acquir Immune Defic Syndr 60:455-61
Martellini, Julie A; Cole, Amy L; Svoboda, Pavel et al. (2011) HIV-1 enhancing effect of prostatic acid phosphatase peptides is reduced in human seminal plasma. PLoS One 6:e16285
Li, Ming; Patton, Dorothy L; Cosgrove-Sweeney, Yvonne et al. (2011) Incorporation of the HIV-1 microbicide cyanovirin-N in a food product. J Acquir Immune Defic Syndr 58:379-84
Sassi, A B; Cost, M R; Cole, A L et al. (2011) Formulation development of retrocyclin 1 analog RC-101 as an anti-HIV vaginal microbicide product. Antimicrob Agents Chemother 55:2282-9
Cole, Alexander M; Patton, Dorothy L; Rohan, Lisa C et al. (2010) The formulated microbicide RC-101 was safe and antivirally active following intravaginal application in pigtailed macaques. PLoS One 5:e15111
Venkataraman, Nitya; Cole, Amy L; Ruchala, Piotr et al. (2009) Reawakening retrocyclins: ancestral human defensins active against HIV-1. PLoS Biol 7:e95
Sivaraman, Karthikeyan; Seshasayee, Aswinsainarain; Tarwater, Patrick M et al. (2008) Codon choice in genes depends on flanking sequence information--implications for theoretical reverse translation. Nucleic Acids Res 36:e16
Sorensen, Ole E; Borregaard, Niels; Cole, Alexander M (2008) Antimicrobial peptides in innate immune responses. Contrib Microbiol 15:61-77
Cole, Alexander M; Cole, Amy Liese (2008) Antimicrobial polypeptides are key anti-HIV-1 effector molecules of cervicovaginal host defense. Am J Reprod Immunol 59:27-34

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