title: C34, a membrane fusion inhibitor, blocks HIV infection of langerhans cells and viral transmission to T cells.
abstract: Development of topical microbicides that prevent sexual transmission of HIV is an active area of investigation. The purpose of this study was to test the ability of the potent membrane fusion inhibitor C34, an HIV gp41 antagonist, to block HIV infection of human Langerhans cells (LCs) in an epithelial environment that mimics a major route of HIV infection. We incubated freshly isolated epidermal explants containing LCs with various doses of C34 before, during, and after exposing explants to HIV. Although C34 only partially blocked HIV infection of LCs when pre-incubated with skin, it displayed full, dose-dependent inhibition when present during and after viral exposure. The poor protection from HIV infectivity in pre-incubated samples is consistent with mechanism of C34 inhibition and starkly contrasts to the full protection provided by PSC-RANTES, an entry inhibitor that prevents HIV gp120 interaction with its co-receptor CCR5. Real-time PCR confirmed that C34 blocked HIV infection of LCs before reverse transcription and inhibited LC-mediated transfer of virus to T cells. We conclude that C34, if used topically at susceptible mucosal sites, and if continually present, has the potential to block sexual transmission of HIV.
authors.affiliation: Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sugaya
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartley
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Root
authors.forename: Andrew
authors.initials: A
authors.lastname: Blauvelt
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology; D018952:Antigens, CD34 / Q000008:administration & dosage*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000031:analogs & derivatives / Q000494:pharmacology; D018920:Coculture Techniques; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology; D015683:Gene Products, gag / Q000235:genetics; D006678:HIV / Q000187:drug effects* / Q000235:genetics; D015700:HIV Envelope Protein gp41 / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000635:transmission*; D006801:Humans; D007801:Langerhans Cells / Q000166:cytology / Q000276:immunology / Q000821:virology*; D008561:Membrane Fusion / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000821:virology*; D016662:Virus Integration / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D018952:Antigens, CD34; D018946:Chemokine CCL5; D015683:Gene Products, gag; D015700:HIV Envelope Protein gp41; C492865:RANTES, N(alpha)-(n-nonanoyl)-desSer(1)-(thioproline(2),cyclohexylglycine(3))-; D015215:Zidovudine