title: Development of an HIV-1 Microbicide Based on Caulobacter crescentus: Blocking Infection by High-Density Display of Virus Entry Inhibitors.
abstract: The HIV/AIDS pandemic remains an enormous global health concern. Despite effective prevention options, 2.6 million new infections occur annually, with women in developing countries accounting for more than half of these infections. New prevention strategies that can be used by women are urgently needed. Topical microbicides specific for HIV-1 represent a promising prevention strategy. Conceptually, using harmless bacteria to display peptides or proteins capable of blocking entry provides an inexpensive approach to microbicide development. To avoid the potential pitfalls of engineering commensal bacteria, our strategy is to genetically display infection inhibitors on a non-native bacterium and rely on topical application of stabilized bacteria before potential virus exposure. Due to the high density cell-surface display capabilities and the inherent low toxicity of the bacterium, the S-layer mediated protein display capabilities of the non-pathogenic bacterium Caulobacter crescentus has been exploited for this approach. We have demonstrated that C. crescentus displaying MIP1α or CD4 interfered with the virus entry pathway and provided significant protection from HIV-1 pseudovirus representing clade B in a standard single cycle infection assay. Here we have expanded our C. crescentus based microbicide approach with additional and diverse classes of natural and synthetic inhibitors of the HIV-1 entry pathway. All display constructs provided variable but significant protection from HIV-1 infection; some with protection as high as 70%. Further, we describe protection from infection with additional viral clades. These findings indicate the significant potential for engineering C. crescentus to be an effective and readily adaptable HIV-1 microbicide platform.
authors.affiliation: Department of Microbiology and Immunology, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Farr
authors.forename: John F
authors.initials: JF
authors.lastname: Nomellini
authors.forename: Evan
authors.initials: E
authors.lastname: Ailon
authors.forename: Iryna
authors.initials: I
authors.lastname: Shanina
authors.forename: Sassan
authors.initials: S
authors.lastname: Sangsari
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cavacini
authors.forename: John
authors.initials: J
authors.lastname: Smit
authors.forename: Marc S
authors.initials: MS
authors.lastname: Horwitz
mesh_terms: D000287:Administration, Topical; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D000891:Anti-Infective Agents, Local / Q000494:pharmacology / Q000627:therapeutic use; D015704:CD4 Antigens / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D016935:Caulobacter crescentus / Q000235:genetics* / Q000378:metabolism; D054405:Chemokine CCL3 / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005818:Genetic Engineering; D015658:HIV Infections / Q000517:prevention & control / Q000628:therapy; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D000891:Anti-Infective Agents, Local; D015704:CD4 Antigens; D054405:Chemokine CCL3; D008562:Membrane Glycoproteins; C055764:S-layer proteins