title: Controlling Multicycle Replication of Live-Attenuated HIV-1 Using an Unnatural Genetic Switch.
abstract: A safe and effective human immunodeficiency virus type 1 (HIV-1) vaccine is urgently needed, but remains elusive. While HIV-1 live-attenuated vaccine can provide potent protection as demonstrated in rhesus macaque-simian immunodeficiency virus model, the potential pathogenic consequences associated with the uncontrolled virus replication preclude such vaccine from clinical applications. We investigated a novel approach to address this problem by controlling live-attenuated HIV-1 replication through an unnatural genetic switch that was based on the amber suppression strategy. Here we report the construction of all-in-one live-attenuated HIV-1 mutants that contain genomic copy of the amber suppression system. This genetic modification resulted in viruses that were capable of multicycle replication in vitro and could be switched on and off using an unnatural amino acid as the cue. This stand-alone, replication-controllable attenuated HIV-1 virus represents an important step toward the generation of a safe and efficacious live-attenuated HIV-1 vaccine. The strategy reported in this work can be adopted for the development of other live-attenuated vaccines.
authors.affiliation: Nebraska Center for Virology & School of Biological Sciences, University of Nebraska-Lincoln , Lincoln, Nebraska 68583, United States.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Chemistry, University of Nebraska-Lincoln , Lincoln, Nebraska 68588, United States.
authors.forename: Nanxi
authors.initials: N
authors.lastname: Wang
authors.affiliation: Nebraska Center for Virology & School of Biological Sciences, University of Nebraska-Lincoln , Lincoln, Nebraska 68583, United States.
authors.forename: Guobin
authors.initials: G
authors.lastname: Kang
authors.affiliation: Department of Chemical & Biomolecular Engineering, University of Nebraska-Lincoln , Lincoln, Nebraska 68588, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Niu
authors.affiliation: Nebraska Center for Virology & School of Biological Sciences, University of Nebraska-Lincoln , Lincoln, Nebraska 68583, United States.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Chemistry, University of Nebraska-Lincoln , Lincoln, Nebraska 68588, United States.
authors.forename: Jiantao
authors.identifier: 0000-0001-6983-9953
authors.initials: J
authors.lastname: Guo
mesh_terms: D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D000604:Amino Acyl-tRNA Synthetases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001386:Azides / Q000737:chemistry; D018388:Codon, Terminator / Q000235:genetics; D005812:Genes, Switch; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008856:Microscopy, Fluorescence; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism; D014613:Vaccines, Attenuated / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology*
chemical_list: D000596:Amino Acids; D001386:Azides; D018388:Codon, Terminator; D014613:Vaccines, Attenuated; C027162:4-azidophenylalanine; D010649:Phenylalanine; D012343:RNA, Transfer; D000604:Amino Acyl-tRNA Synthetases
keywords: HIV-1 vaccine; genetic code; live-attenuated vaccine; unnatural amino acid; virus engineering