Designed oligomers of cyanovirin-N show enhanced HIV neutralization
Abstract
Cyanovirin-N (CV-N) is a small, cyanobacterial lectin that neutralizes many enveloped viruses, including human immunodeficiency virus type I (HIV-1). This antiviral activity is attributed to two homologous carbohydrate binding sites that specifically bind high mannose glycosylation present on envelope glycoproteins such as HIV-1 gp120. We created obligate CV-N oligomers to determine whether increasing the number of binding sites has an effect on viral neutralization. A tandem repeat of two CV-N molecules (CVN_2) increased HIV-1 neutralization activity by up to 18-fold compared to wild-type CV-N. In addition, the CVN_2 variants showed extensive cross-clade reactivity and were often more potent than broadly neutralizing anti-HIV antibodies. The improvement in activity and broad cross-strain HIV neutralization exhibited by these molecules holds promise for the future therapeutic utility of these and other engineered CV-N variants.
Additional Information
© 2011 National Academy of Sciences. Contributed by Stephen L. Mayo, May 31, 2011 (sent for review April 1, 2011). Published online before print July 28, 2011. We thank Leonard Thomas, Pavle Nikolovski, and the Molecular Observatory at Caltech, which is supported by the Gordon and Betty Moore Foundation, for assistance in setting up crystal trays, collecting and processing diffraction data, and refining crystal structures. We also thank the Collaboration for AIDS Vaccine Discovery Neutralizing Antibody Core Laboratories for performing HIV neutralization assays and Marie Ary for critical review of the manuscript. This work was funded by the National Security Science and Engineering Faculty Fellowship program and the Defense Advanced Research Projects Agency Protein Design Processes program (to S.L.M.) and by the Bill and Melinda Gates Foundation Grant 38660 through the Grand Challenges in Global Health Initiative (to P.J.B.). X-ray data for CVN_2L10 were collected at the Stanford Synchrotron Radiation Lightsource (Beam Line 12-2). Operations at Stanford Synchotron Radiation Lightsource are supported by the Department of Energy and the National Institutes of Health. Author contributions: J.R.K., P.J.B., and S.L.M. designed research; J.R.K., P.N.P.G., S.K.G., and J.Y. performed research; J.R.K., P.N.P.G., S.K.G., J.Y., P.J.B., and S.L.M. analyzed data; and J.R.K. wrote the paper. The authors declare no conflict of interest. Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3S3Y, 3S3Z). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1108777108/-/DCSupplemental.Attached Files
Published - Keeffe_2011_Proc_Natl_Acad_Sci_USA_Designed_oligomers_of_cyanovirin-N_show.pdf
Supplemental Material - pnas.1108777108_SI.pdf
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Additional details
- PMCID
- PMC3161612
- Eprint ID
- 25313
- Resolver ID
- CaltechAUTHORS:20110913-132623950
- Gordon and Betty Moore Foundation
- National Security Science and Engineering Faculty Fellowship
- Defense Advanced Research Projects Agency (DARPA)
- Bill and Melinda Gates Foundation
- 38660
- Department of Energy (DOE)
- NIH
- Created
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2011-09-15Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field