The most common route of HIV-1 transmission throughout the world involves sexual contact at mucosal surfaces. Although much attention has been focused on vaccine development for HIV-1, progress has been slow and there is an urgent need to find alternative approaches to target the spread of HIV-1. In our search for novel compounds active against HIV-1 we discovered that certain antimicrobial peptides, the cationic theta-defensins from primates, could effectively inhibit HIV-1 infection in vitro. Although humans no longer produce theta-defensin peptides, human bone marrow provided the 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 named retrocyclin. We determined that retrocyclin and several analogs inhibited viral entry of nearly all X4 and R5 primary isolates and lab-adapted strains of HIV-1 tested so far. The nature of the viral inhibition was specific, in that slight modifications to retrocyclin structure could impart significant variation in anti-HIV-1 activity. Many retrocyclins were essentially non-cytotoxic and non-hemolytic, and thus we have designed peptide analogs with high therapeutic indices. Based on our preliminary studies, we hypothesize that a) retrocyclin analogs will retain activity in human fluids, induce minimal viral resistance, exhibit low cyto- and histotoxicity, and be effective inhibitors of HIV-1 transmission when applied topically to human cervicovaginal organ culture, b) virally-induced IFN-beta is an essential factor that enhances the expression of retrocyclin mRNA, and c) agents such as aminoglycosides, which can suppress the premature termination codon in retrocyclin mRNA, will enable human cells to express functional retrocyclin peptides. With assistance from a multidisciplinary team, we will test these hypotheses by 1) developing retrocyclin analogs that exhibit anti- HIV-1 potency in the vaginal mucosa while minimally inducing viral resistance, and 2) characterizing the regulation of retrocyclin expression and examining the ability to human cells to produce functional retrocyclins that protect against HIV-1 infection. In the aggregate, these studies are natural extensions of our ongoing efforts to characterize and develop retrocyclins as topical agents that prevent mucosal transmission of HIV-1.
TO PUBLIC HEALTH (lay statement): HIV-1 is most commonly spread through sexual contact at mucosal (e.g. vaginal) surfaces. We have discovered a novel molecule called """"""""retrocyclin"""""""" that is active against HIV-1, and are working to develop retrocyclin-based agents that can prevent sexual transmission of HIV-1. Availability of such agents, in the form of a cream or gel, would empower vulnerable sexual partners by providing them with an invisible, effective means of protection.
|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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