title: Toward a live microbial microbicide for HIV: commensal bacteria secreting an HIV fusion inhibitor peptide.
abstract: Most HIV transmission occurs on the mucosal surfaces of the gastrointestinal and cervicovaginal tracts, both of which are normally coated by a biofilm of nonpathogenic commensal bacteria. We propose to genetically engineer such naturally occurring bacteria to protect against HIV infection by secreting antiviral peptides. Here we describe the development and characterization of Nissle 1917, a highly colonizing probiotic strain of Escherichia coli, secreting HIV-gp41-hemolysin A hybrid peptides that block HIV fusion and entry into target cells. By using an appropriate combination of cis- and transacting secretory and regulatory signals, micromolar secretion levels of the anti-HIV peptides were achieved. The genetically engineered Nissle 1917 were capable of colonizing mice for periods of weeks to months, predominantly in the colon and cecum, with lower concentrations of bacteria present in the rectum, vagina, and small intestine. Histological and immunocytochemical examination of the colon revealed bacterial growth and peptide secretion throughout the luminal mucosa and in association with epithelial surfaces. The use of genetically engineered live microbes as anti-HIV microbicides has important potential advantages in economy, efficacy, and durability.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Laboratories of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Rao
authors.forename: Stella
authors.initials: S
authors.lastname: Hu
authors.forename: Louise
authors.initials: L
authors.lastname: McHugh
authors.forename: Kira
authors.initials: K
authors.lastname: Lueders
authors.forename: Ken
authors.initials: K
authors.lastname: Henry
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Richard A
authors.initials: RA
authors.lastname: Fekete
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Kar
authors.forename: Sankar
authors.initials: S
authors.lastname: Adhya
authors.forename: Dean H
authors.initials: DH
authors.lastname: Hamer
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D002432:Cecum / Q000382:microbiology; D003106:Colon / Q000382:microbiology; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005818:Genetic Engineering / Q000379:methods*; D006678:HIV / Q000187:drug effects* / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000378:metabolism*; D015658:HIV Infections / Q000517:prevention & control*; D006460:Hemolysin Proteins / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000382:microbiology; D051379:Mice; D008954:Models, Biological; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D014621:Vagina / Q000382:microbiology
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D006460:Hemolysin Proteins; D010455:Peptides