3rd International AIDS Society Conference on HIV Pathogenesis and Treatment Rio de Janeiro - July 24 - 27, 2005

USING LIVE MICROBES AS ANTI-HIV MICROBICIDES

IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract No. MoPp0101

Hamer D.¹, Henry K.¹, Hu S.¹, McHugh L.¹, Lueders K.¹, Adhya S.¹, Rao S.^2
1NCI, National Institutes of Health, Bethesda, United States of America, ²Vaccine Research Center, National Institutes of Health, Bethesda, United States of America

INTRODUCTION: Although topical microbicides are a promising approach for preventing HIV transmission, their utility is hampered by the need for frequent application. Most HIV transmission occurs on the mucosal surfaces of the gastrointestinal and cervico-vaginal tracts, which are normally coated by a biofilm of nonpathogenic commensal bacteria. We propose to genetically engineer such naturally occurring bacteria to secrete peptides that block viral infection or replication. Introduction of such genetically modified organisms into uninfected individuals under conditions where they colonize the mucosa would provide a long lasting bioshield against HIV.

METHODS: Nissle 1917, a highly colonizing probiotic strain of E. coli, was genetically engineered to secrete HIV-gp41 C peptides through the hemolysin A type I secretion pathway. The modified bacteria were tested for growth and functional peptide expression in vitro and in vivo.

RESULTS: By using a suitable combination of cis- and trans-acting secretory and regulatory signals, micromolar levels of the anti-HIV peptides were secreted. In vitro, the genetically engineered Nissle 1917 specifically and potently blocked infection of T cells and macrophage by a wide spectrum of primary isolates of HIV. In vivo, these strains colonized mice for periods of weeks to months, predominantly in the colon and cecum, with lower concentrations present in the rectum, vagina and small intestine. Histological and immunocytochemical examination revealed dense bacterial growth along the colonic lumen, epithelial association of the bacteria, and abundant peptide secretion into the mucosa.

CONCLUSIONS: Our results show that genetically engineered bacteria can (1) synthesize and secrete sufficient quantities of potent and broadly active HIV inhibitory compounds to block infection by diverse HIV primary isolates, and (2) compete with indigenous microbes for prolonged colonization of mucosal surfaces. The use of genetically engineered live microbes as anti-HIV microbicides has important advantages in economy, efficacy and durability.

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Prevention | MoPp0101 | Dean Hamer
10.8 237 10.8 Microbicides

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