Scientists working in The Skaggs Institute for Chemical Biology at The Scripps Research Institute (TSRI) and at the Glycobiology Institute at Oxford University in the United Kingdom, have elucidated the structure of an antibody that effectively neutralizes human immunodeficiency virus (HIV), reported in the current issue of the journal Science. Designated b12, the antibody has a long finger-like region on its surface that penetrates the surface of the main viral glycoprotein gp120 on the HIV virus and prevents it from causing disease. The authors hope that the structure of this region will provide a basis for the design of effective vaccines against the HIV virus.
"A lot of people in the HIV field are excited by this structure," says Professor Ian Wilson, D. Phil., of the The Skaggs Institute and Department of Molecular Biology. "It clearly illustrates the sort of antibody you need to raise in order to have an effective vaccine against HIV."
HIV causes AIDS by binding to, entering, and, ultimately, leading to the killing of certain blood cells—distinguished by a certain protein, called CD4, that these cells carry on their surfaces. T cells and macrophages, which both carry CD4, are necessary to fight off infections by common bacteria and other pathogens, and these pathogens become potentially lethal to patients after their own immune system destroys the infected CD4 cells.
One of the most compelling medical challenges today is to develop a vaccine that will provide complete prophylactic protection to someone who is later exposed to this virus.
An important part of such a vaccine will be an effective neutralizing antibody against HIV.
Also called immunoglobins, these antibodies would be produced by the body's B cells after HIV enters the bloodstream. During such an immune response, the antibodies would circulate through the blood, and track down and kill the virus.
Normally, the antibodies that the body produces to fight HIV are ineffective because much of the surface of the virus is inaccessible.
"HIV is coated with carbohydrates," says scientist Erica Ollmann Saphire, Ph.D., who is first author on the paper. "They cloak the virus."
Even worse, antibodies mostly recognize long protein loops on the outside of the virus, and in the body HIV rapidly mutates so that these loops become unrecognizable. The antibody b12, though, appears to be effective against a wide variety of HIV isolates. This is because it binds to part of the HIV that cannot mutate—the region of the virus that must bind to CD4. The antibody neutralizes the virus, making it unable to invade cells. A further problem is that the virus sheds its cell surface gp120 and antibodies raised against this viral debris are ineffective against the intact virus. Thus, the shed viral proteins act as a decoy to divert the immune response from the virus itself.
First identified in the bone marrow of a 31-year-old male who had been HIV positive without symptoms for six years, b12 demonstrates the human immune system is capable of raising antibodies that are effective against HIV, and scientists will now be investigating the ways in which this type of immune response can be triggered.
Another notable fact about this accomplishment is that this structure is the first human antibody to be solved in its entirety. Normally, scientists only solve a piece of an antibody—the fragment at the end—because whole antibodies do not form good crystals, an important first step in solving a structure. But by working with an antibody preparation that was unusually pure, the team managed to make crystals and solve the structure.
The research article, "Crystal Structure of a Neutralizing Human IgG Against HIV-1: A Template for Vaccine Design" is authored by Erica Ollmann Saphire, Paul W.H.I. Parren, Ralph Pantophlet, Michael B. Zwick, Robyn L. Stanfield, Garrett M. Morris, Pauline M. Rudd, Raymond A. Dwek, Dennis R. Burton, and Ian A. Wilson, and appears in the August 10, 2001 issue of the journal Science.
The research was funded in part by the National Institutes of Health and The Skaggs Institute for Research.
Materials provided by Scripps Research Institute. Note: Content may be edited for style and length.
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