Antigen SynthesisA Step Forward Towards an AIDS Vaccine
By Jason Socrates Bardi
The outlook for acquired immunodeficiency syndrome (AIDS) worldwide is bleak.
The World Health Organization estimates that around 40 million people worldwide are already living with the human immunodeficiency virus (HIV), which causes AIDS. During 2001 alone, more than four million men, women, and children succumbed to the disease, and by the end of that year, the disease had made orphans of 14 million children. In the United States, 40,000 people are infected with HIV each year.
One of our best hopes to stem this rising tide of infection is to develop a vaccine against HIV. Vaccines have done wonders to control diseases like measles and polio in much of the world, and in the 1970s, vaccines were instrumental in eradicating smallpox. Almost since the first days of HIV research in the 1980s, government agencies, foundations, and private companies have supported efforts to develop vaccines to protect against HIVso far without success.
Now a team of scientists at The Scripps Research Institute has taken a step forward on this long road. In a recent issue of the scientific journal Angewandte Chemie, the team has defined details of the action of an antibody that broadly neutralizes HIV. Last year Scripps Research Immunology Professor Dennis Burton and Molecular Biology Professor Ian Wilson described the structure of the antibody, which is called 2G12.
The 2G12 antibody recognizes a dense cluster of mannose sugars on one region of the surface glycoprotein of HIV. This region is conserved (invariant) in many strains of HIV, which is why the antibody is able to broadly neutralize the virus. Approximately half of the world's viruses are neutralized by the antibody. It was originally identified from an HIV-positive individual about a decade ago by Hermann Katinger, a doctor at the Institute for Applied Microbiology of the University of Agriculture in Vienna, Austria.
In the current study, Burton and Wilson teamed up with Scripps Research Chemistry Professor Chi-Huey Wong to design and test synthetic constructs that would mimic the cluster of sugars recognized by 2G12 and would constitute a potential vaccine lead.
Using a technique Wong invented called programmable one-pot synthesis, the Scripps Research team designed several novel mannose compounds that bind to 2G12. The one-pot technique allows Wong to quickly assemble many types of carbohydrate structures by placing a large number of specific chemical building blocks into a reaction vessel and then making sequential chemical reactions in the soup.
Burton says that the synthesis of these antigen-like compounds is the first stage of an approach that he likes to call "retrovaccinology," which works backward from the antibody to the vaccine. The hope is that the information reaped from the study of how these synthetic compounds bind to the 2G12 antibody could eventually be used to make a prophylactic vaccine to protect people against HIV infection.
To read the article, "Reactivity-Based One-Pot Synthesis of Oligomannoses: Defining Antigens Recognized by 2G12, a Broadly Neutralizing anti-HIV-1 Antibody" by Hing-Ken Lee, Christopher N. Scanlan, Cheng-Yuan Huang, Aileen Y. Chang, Daniel A. Calarese, Raymond A. Dwek, Pauline M. Rudd, Dennis R. Burton, Ian. A.Wilson, and Chi-HueyWong, please see the February 13, 2004 issue of Angewandte Chemie (2004, 43, 1000-1003) or go to: http://dx.doi.org/10.1002/anie.200353105.
The research was supported by The Skaggs Institute for Research, by grants from the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of General Medical Sciences (NIGMS), by the International AIDS Vaccine Initiative (IAVI), and by the Pendleton Trust.
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