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: Ron Diskin, Florian Klein, Joshua A Horwitz, Ariel Halper-Stromberg, D Noah Sather, Paola M Marcovecchio, Terri Lee, Anthony P West Jr, Han Gao, Michael S Seaman, Leonidas Stamatatos, Michel C Nussenzweig, Pamela J Bjorkman
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 210 Issue 6 Pg. 1235-49 (Jun 03 2013) ISSN: 1540-9538 [Electronic] United States
• PMID: 23712429 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• AIDS Vaccines
• Antibodies, Neutralizing
• HIV Antibodies
• HIV Envelope Protein gp120
• gp120 protein, Human immunodeficiency virus 1

Topics

• AIDS Vaccines (genetics, immunology)
• Animals
• Antibodies, Neutralizing (genetics, immunology)
• Cell Line
• HEK293 Cells
• HIV Antibodies (genetics, immunology)
• HIV Envelope Protein gp120 (genetics, immunology)
• HIV Infections (genetics, immunology)
• HIV-1 (genetics, immunology)
• Humans
• Mice
• Mutation (genetics, immunology)
• Structure-Activity Relationship