title: Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection.
abstract: Recent in vitro studies have demonstrated that amyloid fibrils found in semen from healthy and HIV-infected men, as well as semen itself, can markedly enhance HIV infection rates. Semen fibrils are made up of multiple naturally occurring peptide fragments derived from semen. The best characterized of these fibrils are SEVI (semen-derived enhancer of viral infection), made up of residues 248-286 of prostatic acidic phosphatase, and the SEM1 fibrils, made up of residues 86-107 of semenogelin 1. A small molecule screen for antagonists of semen fibrils identified four compounds that lowered semen-mediated enhancement of HIV-1 infectivity. One of the four, gallic acid, was previously reported to antagonize other amyloids and to exert anti-inflammatory effects. To better understand the mechanism by which gallic acid modifies the properties of semen amyloids, we performed biophysical measurements (atomic force microscopy, electron microscopy, confocal microscopy, thioflavin T and Congo Red fluorescence assays, zeta potential measurements) and quantitative assays on the effects of gallic acid on semen-mediated enhancement of HIV infection and inflammation. Our results demonstrate that gallic acid binds to both SEVI and SEM1 fibrils and modifies their surface electrostatics to render them less cationic. In addition, gallic acid decreased semen-mediated enhancement of HIV infection but did not decrease the inflammatory response induced by semen. Together, these observations identify gallic acid as a non-polyanionic compound that inhibits semen-mediated enhancement of HIV infection and suggest the potential utility of incorporating gallic acid into a multicomponent microbicide targeting both the HIV virus and host components that promote viral infection.
authors.affiliation: Center for Biotechnology and Interdisciplinary Studies and Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York 12180.
authors.forename: Josephine G
authors.initials: JG
authors.lastname: LoRicco
authors.affiliation: Center for Biotechnology and Interdisciplinary Studies and Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York 12180.
authors.forename: Changmingzi Sherry
authors.initials: CS
authors.lastname: Xu
authors.affiliation: Gladstone Institute of Virology and Immunology, San Francisco, California 94158.
authors.forename: Jason
authors.initials: J
authors.lastname: Neidleman
authors.affiliation: Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York 12203.
authors.forename: Magnus
authors.initials: M
authors.lastname: Bergkvist
authors.affiliation: Gladstone Institute of Virology and Immunology, San Francisco, California 94158.
authors.forename: Warner C
authors.initials: WC
authors.lastname: Greene
authors.affiliation: Gladstone Institute of Virology and Immunology, San Francisco, California 94158,; Department of Urology, University of California, San Francisco, California 94158. Electronic address: nadia.roan@ucsf.edu.
authors.forename: Nadia R
authors.initials: NR
authors.lastname: Roan
authors.affiliation: Center for Biotechnology and Interdisciplinary Studies and Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York 12180,. Electronic address: makhag@rpi.edu.
authors.forename: George I
authors.initials: GI
authors.lastname: Makhatadze
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000187:drug effects*; D005707:Gallic Acid / Q000494:pharmacology*; D015658:HIV Infections / Q000503:physiopathology* / Q000821:virology; D015497:HIV-1; D006801:Humans; D008297:Male; D008853:Microscopy / Q000379:methods; D012661:Semen / Q000378:metabolism*
chemical_list: D000682:Amyloid; D005707:Gallic Acid
keywords: HIV-1; SEVI; Semen; Semenogelin; amyloid; atomic force microscopy (AFM); biophysics; confocal microscopy; fluorescence