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PDBsum entry 4jkp
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Viral protein/immune system
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PDB id
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4jkp
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Contents |
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340 a.a.
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222 a.a.
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207 a.a.
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References listed in PDB file
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Key reference
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Title
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Restricting HIV-1 pathways for escape using rationally designed anti-Hiv-1 antibodies.
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Authors
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R.Diskin,
F.Klein,
J.A.Horwitz,
A.Halper-Stromberg,
D.N.Sather,
P.M.Marcovecchio,
T.Lee,
A.P.West,
H.Gao,
M.S.Seaman,
L.Stamatatos,
M.C.Nussenzweig,
P.J.Bjorkman.
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Ref.
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J Exp Med, 2013,
210,
1235-1249.
[DOI no: ]
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PubMed id
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Abstract
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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.
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