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J Exp Med. 2013 Jun 3;210(6):1235-49. doi: 10.1084/jem.20130221. Epub 2013 May 27.

Restricting HIV-1 pathways for escape using rationally designed anti-HIV-1 antibodies.

Author information

1
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA. ron.diskin@weizmann.ac.il

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.

PMID:
23712429
PMCID:
PMC3674693
DOI:
10.1084/jem.20130221
[Indexed for MEDLINE]
Free PMC Article

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