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

R Diskin, F Klein, JA Horwitz… - Journal of Experimental …, 2013 - rupress.org
R Diskin, F Klein, JA Horwitz, A Halper-Stromberg, DN Sather, PM Marcovecchio, T Lee…
Journal of Experimental Medicine, 2013rupress.org
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 NIH45-46G54W, which exhibits
superior potency and/or breadth compared with other bNAbs. We report new, more effective …
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 NIH45-46G54W, which exhibits superior potency and/or breadth compared with other bNAbs. We report new, more effective NIH45-46G54W variants designed using analyses of the NIH45-46–gp120 complex structure and sequences of NIH45-46G54W–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 NIH45-46G54W 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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