ScienceDaily (June 3, 2010) — In findings that contribute to efforts to design an AIDS vaccine, a team led by Scripps Research Institute scientists has determined the structure of an immune system antibody molecule that effectively acts against most strains of human immunodeficiency virus (HIV), the virus that causes AIDS.
The new study reveals the structure of an unusual human antibody against HIV called PG16.
Credit: Image courtesy of Scripps Research Institute)
"This study advances the overall goal of how to design an HIV vaccine," said Scripps Research Professor Ian Wilson, who led the team with Dennis Burton, Scripps Research professor and scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at Scripps Research. "This antibody is highly effective in neutralizing HIV-1 and has evolved novel features to combat the virus."
The Problem with HIV
According to the World Health Organization's latest statistics, around 33 million people are living with HIV worldwide. During 2008 alone, more than 2 million men, women, and children succumbed to the disease and an estimated 2.7 million were infected with HIV. One of the most compelling medical challenges today is to develop a vaccine that will provide complete protection to someone who is later exposed to this virus.
HIV causes AIDS by binding to, entering, and ultimately leading to the death of T helper cells, which are immune cells that are necessary to fight off infections by common bacteria and other pathogens. As HIV depletes the body of T helper cells, common pathogens can become potentially lethal.
An effective HIV vaccine would induce antibodies (specialized immune system molecules) against the virus prior to exposure to the virus. Also called immunoglobulins, these antibodies would circulate through the blood, and track down and kill the virus.
Most of the antibodies that the body produces to fight HIV, however, are ineffective. The surface of the virus is cloaked with sugar molecules that prevent antibodies from slipping in and blocking the proteins the virus uses to latch onto a cell and infect it. To make matters more complicated, HIV is constantly mutating, so there are multiple HIV strains that antibodies elicited in any vaccine must be able to sense and destroy.
Nonetheless, while rare, broadly neutralizing antibodies against HIV do exist.
Last year, a team of scientists from IAVI, Scripps Research, Theraclone Sciences, and Monogram Biosciences published research from a systematic search for such antibodies among 2,000 volunteers. The study revealed two powerful new broadly neutralizing antibodies against HIV -- PG9 and PG16, isolated from a volunteer in Africa.
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Structure and function of broadly reactive antibody PG16 reveal an H3 subdomain that mediates potent neutralization of HIV-1
Robert Pejchal a, Laura M. Walker b, Robyn L. Stanfield a, Sanjay K. Phogat c, Wayne C. Koff c, Pascal Poignard b,d, Dennis R. Burton b,d,e,1, and Ian A. Wilson a,d,f,1
-Author Affiliations
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Structure and function of broadly reactive antibody PG16 reveal an H3 subdomain that mediates potent neutralization of HIV-1
Robert Pejchal a, Laura M. Walker b, Robyn L. Stanfield a, Sanjay K. Phogat c, Wayne C. Koff c, Pascal Poignard b,d, Dennis R. Burton b,d,e,1, and Ian A. Wilson a,d,f,1
-Author Affiliations
a Departments of aMolecular Biology and
b Immunology and Microbial Science,
d International AIDS Vaccine Initiative Neutralizing Antibody Center, and
f The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037;
c International AIDS Vaccine Initiative, New York, NY 10038; and
e Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, MA 02114
Edited by David Baker, University of Washington, Seattle, WA, and approved May 7, 2010 (received for review April 6, 2010)
Abstract
Development of an effective vaccine against HIV-1 will likely require elicitation of broad and potent neutralizing antibodies against the trimeric surface envelope glycoprotein (Env). Monoclonal antibodies (mAbs) PG9 and PG16 neutralize ~80% of HIV-1 isolates across all clades with extraordinary potency and target novel epitopes preferentially expressed on Env trimers. As these neutralization properties are ideal for a vaccine-elicited antibody response to HIV-1, their structural basis was investigated. The crystal structure of the antigen-binding fragment (Fab) of PG16 at 2.5 Å resolution revealed its unusually long, 28-residue, complementarity determining region (CDR) H3 forms a unique, stable subdomain that towers above the antibody surface. A 7-residue “specificity loop” on the “hammerhead” subdomain was identified that, when transplanted from PG16 to PG9 and vice versa, accounted for differences in the fine specificity and neutralization of these two mAbs. The PG16 electron density maps also revealed that a CDR H3 tyrosine was sulfated, which was confirmed for both PG9 (doubly) and PG16 (singly) by mass spectral analysis. We further showed that tyrosine sulfation plays a role in binding and neutralization. An N-linked glycan modification is observed in the variable light chain, but not required for antigen recognition. Further, the crystal structure of the PG9 light chain at 3.0 Å facilitated homology modeling to support the presence of these unusual features in PG9. Thus, PG9 and PG16 use unique structural features to mediate potent neutralization of HIV-1 that may be of utility in antibody engineering and for high-affinity recognition of a variety of therapeutic targets.
neutralizing antibody PG9 sulfotyrosine gp120 Env
Footnotes
1To whom correspondence may be addressed. E-mail: burton@scripps.edu orwilson@scripps.edu.
Author contributions: R.P., L.M.W., S.K.P., W.C.K., D.R.B., and I.A.W. designed research; R.P. and L.M.W. performed research; R.P. and L.M.W. contributed new reagents/analytic tools; R.P., L.M.W., R.L.S., P.P., D.R.B., and I.A.W. analyzed data; and R.P., L.M.W., D.R.B., and I.A.W. wrote the paper.
Conflict of interest statement: L.M.W, S.K.P, P.P, and D.R.B. are inventors on a patent describing the human broadly neutralizing antibodies PG9 and PG16 (United States provisional patent application numbers USSN 61/161,010; USSN 61/165,829; and USSN 61/224,739).
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org [PDB ID codes 3MUG (PG16 Fab) and 3MUH (PG9 LC)].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1004600107/-/DCSupplemental.
Freely available online through the PNAS open access option.
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org [PDB ID codes 3MUG (PG16 Fab) and 3MUH (PG9 LC)].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1004600107/-/DCSupplemental.
Freely available online through the PNAS open access option.
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