4JKP

Restricting HIV-1 Pathways for Escape using Rationally-Designed Anti-HIV-1 Antibodies

Summary for 4JKP

• Entry DOI: 10.2210/pdb4jkp/pdb
• Descriptor: gp120, Heavy chain of antibody 45-46M2, Light chain of antibody 45-46M2, ... (8 entities in total)
• Functional Keywords: igg, antibody, gp120, viral protein-immune system complex, viral protein/immune system
• Biological source: Human immunodeficiency virus 1 (HIV); More
• Total number of polymer chains: 3
• Total formula weight: 92175.91

Authors

Diskin, R.,Bjorkman, P.J. (deposition date: 2013-03-11, release date: 2013-05-15, Last modification date: 2024-10-30)

Primary citation

Diskin, R.,Klein, F.,Horwitz, J.A.,Halper-Stromberg, A.,Sather, D.N.,Marcovecchio, P.M.,Lee, T.,West, A.P.,Gao, H.,Seaman, M.S.,Stamatatos, L.,Nussenzweig, M.C.,Bjorkman, P.J.
Restricting HIV-1 pathways for escape using rationally designed anti-HIV-1 antibodies.
J.Exp.Med., 210:1235-1249, 2013

PubMed 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.

PubMed: 23712429
DOI: 10.1084/jem.20130221

Experimental method

X-RAY DIFFRACTION (2.82 Å)