Self-applied prophylactic agents to prevent mucosal, particularly vaginal or rectal, transmission of HIV-1 have the advantage of empowering vulnerable receptive partners to take effective measures for their own protection. In our search for molecules that would be ideal templates for microbicide development, we utilized solid-phase peptide synthesis to recreate an evolutionary lost human antimicrobial peptide """"""""retrocyclin"""""""" from its remains, a theta-defensin pseudogene. The ability of retrocyclin to potently prevent infection of CD4+ cells by both X4 and R5 HIV-1 was remarkable. Additional studies revealed that retrocyclin inhibits the initial steps in HIV-1 binding and entry as its mode of action. Next-generation analogs of retrocyclin were found to be active against numerous primary isolates from most groups and subtypes of HIV-1. Importantly, we have identified a lead compound, RC-101, that is highly active against HIV-1, non-cytotoxic, and suitable for preclinical development as a topical microbicide. Based on our studies, we have formed several hypotheses about retrocyclins: A) retrocyclins will likely function to inhibit HIV-1 infection in the vaginal mucosa, B) the glycosylated targets of retrocyclins and cyanovirin N, another potent anti-HIV-1 lectin (Project 1), are different and thus their activities may be complementary, and C) retrocyclins are potent antiretroviral agents suitable for further development as topical vaginal microbicides to prevent HIV transmission. To test these hypotheses, we propose to: 1) Construct and characterize next-generation analogs of anti-HIV retrocyclins, 2) Evaluate candidate retrocyclin formulations for anti-HIV-1 activity, stability and cytotoxicity, and 3) Evaluate candidate retrocyclin formulations for biologic efficacy in human vaginal fluid and serum. While it may be speculative to assert that the evolutionary loss of retrocyclin contributed to the susceptibility of humans to HIV-1 infection, retrocyclins are promising leads for designing naturally occuring microbicides that can prevent HIV infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI065430-01
Application #
6955868
Study Section
Special Emphasis Panel (ZRG1-AARR-A (50))
Project Start
2005-07-01
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$191,993
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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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