Recently, we discovered serendipitously that certain circular minidefensins, antimicrobial peptides structurally related to the theta-defensins recently described in rhesus macaques, potently inhibit HIV-1 infection in vitro. Although humans no longer produce circular minidefensins, human bone marrow provides evidence - in the form of an expressed pseudogene - that these peptides were once part of our genomic heritage. Using the sequence information still encoded within its expressed pseudogene, we recreated this lost human peptide which we have named retrocyclin. Retrocyclin proved to be a more effective antiretroviral than its rhesus counterparts, potently preventing infection of CD4+ cells by both T-and M-tropic HIV-1. Because it is a small (18 residue) and well-defined molecule, retrocyclin is a promising lead compound for designing topical agents that can be used to prevent human HIV-1 infections. Based on our preliminary studies, we hypothesize that retrocyclin a) acts by inhibiting viral attachment, fusion or entry; b) will inhibit HIV-1 infection in the mucosa and be active in mucosal fluids, and c) is a leading candidate for development as a topical vaginal or rectal microbicide to prevent HIV transmission. With assistance from a multidisciplinary team of immunologists, retrovirologists, and a peptide chemist, we will test these hypotheses by 1) characterizing determinants of retrocyclin activity and identifying the molecular target(s) for its potent inhibitory effects on HIV-1 infection, 2) characterizing structural determinants of retrocyclin activity through the rational design and testing of retrocyclin congeners, and 3) determining the stability of retrocyclin and congeners in human fluids. Such findings could elucidate novel mechanisms of natural resistance to HIV-1 and promote the development of novel, host-compatible antiretrovirals to prevent HIV infection. Because progress in developing an effective vaccine for HIV-1 has been slow, there is an urgent need to find alternative preventive approaches. Our long term goal is to develop the basic information needed to develop topical agents that prevent mucosal (particularly vaginal or rectal) transmission of HIV-1. Availability of such agents, in the form of retrocyclin-containing creams or gels, would empower vulnerable sexual partners by providing them with an invisible, effective means of protection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI052017-01A1
Application #
6553586
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Black, Roberta J
Project Start
2002-05-15
Project End
2006-04-30
Budget Start
2002-05-15
Budget End
2003-04-30
Support Year
1
Fiscal Year
2002
Total Cost
$343,313
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
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
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
Micewicz, Ewa D; Cole, Amy L; Jung, Chun-Ling et al. (2010) Grifonin-1: a small HIV-1 entry inhibitor derived from the algal lectin, Griffithsin. PLoS One 5:e14360

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