title: Restricting HIV-1 pathways for escape using rationally designed anti-HIV-1 antibodies.
abstract: Recently identified broadly neutralizing antibodies (bNAbs) that potently neutralize most HIV-1 strains are key to potential antibody-based therapeutic approaches to combat HIV/AIDS in the absence of an effective vaccine. Increasing bNAb potencies and resistance to common routes of HIV-1 escape through mutation would facilitate their use as therapeutics. We previously used structure-based design to create the bNAb NIH45-46(G54W), which exhibits superior potency and/or breadth compared with other bNAbs. We report new, more effective NIH45-46(G54W) variants designed using analyses of the NIH45-46-gp120 complex structure and sequences of NIH45-46(G54W)-resistant HIV-1 strains. One variant, 45-46m2, neutralizes 96% of HIV-1 strains in a cross-clade panel and viruses isolated from an HIV-infected individual that are resistant to all other known bNAbs, making it the single most broad and potent anti-HIV-1 antibody to date. A description of its mechanism is presented based on a 45-46m2-gp120 crystal structure. A second variant, 45-46m7, designed to thwart HIV-1 resistance to NIH45-46(G54W) arising from mutations in a gp120 consensus sequence, targets a common route of HIV-1 escape. In combination, 45-46m2 and 45-46m7 reduce the possible routes for the evolution of fit viral escape mutants in HIV-1YU-2-infected humanized mice, with viremic control exhibited when a third antibody, 10-1074, was added to the combination.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA. ron.diskin@weizmann.ac.il
authors.forename: Ron
authors.initials: R
authors.lastname: Diskin
authors.forename: Florian
authors.initials: F
authors.lastname: Klein
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Horwitz
authors.forename: Ariel
authors.initials: A
authors.lastname: Halper-Stromberg
authors.forename: D Noah
authors.initials: DN
authors.lastname: Sather
authors.forename: Paola M
authors.initials: PM
authors.lastname: Marcovecchio
authors.forename: Terri
authors.initials: T
authors.lastname: Lee
authors.forename: Anthony P
authors.initials: AP
authors.lastname: West
authors.forename: Han
authors.initials: H
authors.lastname: Gao
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Bjorkman
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics / Q000276:immunology; D013329:Structure-Activity Relationship
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1