D106 Overcoming HIV pathways for escape using rationally-designed anti-HIV antibodies.

Diskin, Ron; Sather, D. Noah; Marcovecchio, Paola M; Lee, Terri; West, Anthony P. Jr; Gao, Han; Klein, Florian; -Halper-Stromberg, Ari; Horwitz, Joshua; Seaman, Michael S.; Stamatatos, Leonidas; Nussenzweig, Michel C.; Bjorkman, Pamela J.
JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/01.qai.0000429234.07501.af
Abstracts: PDF Only

A completely protective vaccine against HIV has not been found, thus possible prevention/treatment options involving delivery of broadly neutralizing antibodies (bNAbs) identified in a minority of HIV-infected individuals are being considered. bNAbs that target conserved epitopes on the HIV envelope spike can prevent infection in animal models, delay rebound of HIV after cessation of anti-retroviral drugs, and treat an ongoing infection9. Enhancing the efficacy of bNAbs; in particular, designing bNAbs that retain potency against escape mutants selected during exposure to bNAbs, would facilitate their use as therapeutics. We previously used structure-based design to create NIH45-46G54W, a CD4-binding site (CD4bs) antibody with superior potency and/or breadth compared with other bNAbs. Here we report even more effective variants of NIH45-46G54W designed using analyses of the NIH45-46/gp120 complex structure and sequences of antibody-resistant HIV clones. One mutant, 45-46m2, neutralizes 96% of HIV 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 antibody to date. A detailed description of its mechanism is presented based on a 45-46m2/gp120 crystal structure. A second mutant, 45-46m7, designed to thwart resistance from NIH45-46G54W due to mutations in a V5/loop D gp120 consensus sequence, restores neutralization of HIV consensus sequence mutants, thus effectively targeting a common route of HIV escape. In combination, almost all HIV isolates are effectively neutralized, reducing the possible routes for the evolution of fit viral escape mutants.

(C) 2013 Lippincott Williams & Wilkins, Inc.