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Engineering Improved Antibodies Against HIV

Bjorkman, Pamela (2014) Engineering Improved Antibodies Against HIV. Protein Science, 23 (S1). pp. 62-63. ISSN 0961-8368. http://resolver.caltech.edu/CaltechAUTHORS:20140822-071326120

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Abstract

Over 30 years after the emergence of HIV-1, there is no effective vaccine, and AIDS remains an important threat to global public health. Following infection by HIV-1, the host immune response is unable to clear the virus due to a variety of factors, including rapid viral mutation and the establishment of latent reservoirs. The only target of neutralizing antibodies is the trimeric envelope (Env) spike complex, but HIV- 1 can usually evade anti-spike antibodies due to rapid mutation of its two spike glycoproteins, gp120 and gp41, and structural features that allow the spike to hide conserved epitopes. Because a completely protective vaccine against HIV has not been found, 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 infection. 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://onlinelibrary.wiley.com/doi/10.1002/pro.2504/abstractPublisherArticle
http://dx.doi.org/10.1002/pro.2504DOIArticle
ORCID:
AuthorORCID
Bjorkman, Pamela0000-0002-2277-3990
Additional Information:© 2014 The Protein Society. Article first published online: 10 Jul 2014.
Record Number:CaltechAUTHORS:20140822-071326120
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20140822-071326120
Official Citation:Protein Science Special Issue: The 28th Annual Symposium of The Protein Society, San Diego, CA, USA, July 27–30, 2014 Volume 23, Issue S1, pages 1–284, July 2014
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:48787
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:22 Aug 2014 20:16
Last Modified:24 Mar 2017 20:21

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