Determination Of Structure Of Immune Molecule That Counteracts HIV Strains Advance The Effort To Develop An AIDS Vaccine

In findings that grant to efforts to design each AIDS vaccine, a team led through Scripps Research Institute scientists has determined the structure of an immune system antibody ultimate particle that effectively acts against most strains of full of habitual human feeling immunodeficiency virus (HIV), the virus that causes AIDS.

The study, which is being published in an send, online delivery of the journal Proceedings of the National Academy of Sciences (PNAS) during the week of June 1, 2010, illuminates every unusual human antibody called PG16.

“This close attention advances the overall goal of how to design each 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 very much effective in neutralizing HIV-1 and has evolved tale features to action 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 only, more than 2 million men, women, and children succumbed to the ail and an estimated 2.7 million were infected by HIV. One of the in the greatest degree compelling medical challenges today is to develop a vaccine that have a mind provide thorough protection to someone who is later exposed to this virus.

HIV causes AIDS by cover to, entering, and ultimately leading to the death of T helper cells, which are immune cells that are necessary to contend off infections by common bacteria and other pathogens. As HIV depletes the body of T colleague cells, common pathogens can become potentially lethal.

An effective HIV vaccine would incite antibodies (specialized immune plan molecules) against the virus prior to exposure to the virus. Also called immunoglobulins, these antibodies would circulate through the descent, and trail on the ground and kill the poison.

Most of the antibodies that the body produces to take up arms HIV, however, are inefficacious.. The surface of the poison is cloaked through sugar molecules that obstruct antibodies from slipping in and blocking the proteins the virus uses to latch onto a small cavity and vitiate it. To make matters greater degree complicated, HIV is constantly mutating, so there are multiple HIV strains that antibodies elicited in any vaccine mould be able to sense and ravage with fire and sword.

Nonetheless, while out of the way, broadly neutralizing antibodies off HIV do have life.

Last year, a team of scientists from IAVI, Scripps Research, Theraclone Sciences, and Monogram Biosciences published research from a systematic search for such antibodies in the midst of 2,000 volunteers. The contemplate revealed two powerful new broadly neutralizing antibodies opposite to HIV – PG9 and PG16, detached from a volunteer in Africa.

“Hammerhead” Structure

Once the broadly neutralizing antibodies were discovered, the next call to answer was to figure loudly how they worked. To shed light on this question, in the current study members of the Wilson lab turned to x-ray crystallography, a technique that can solve structures to exquisitely boisterous resolution.

In x-ray crystallography, scientists manipulate a protein or some other molecule so that a crystal forms. This crystal is then placed in front of a beam of x-rays, which diffract when they ratify the atoms in the crystal. Based on the follow of diffraction, scientists have power to rebuild the appearance of the original molecule. The scientists succeeded in forming crystals of the active part of the PG16 antibody, and in reconstructing the structure from the data – with some unexpected results.

“The antibody has a novel and really interesting subdomain that hasn’face to face been seen before,” said Research Associate Rob Pejchal, who is first original of the paper. “This subdomain, that we found plays a major role in the remembrance and neutralization of HIV, has a different kind of antibody architecture. We like to call it the ‘hammerhead’ since it resembles the head of a hammerhead shark. It reaches out from the main lot of the antibody and it has sum of two units flat ends on top.”

Co-author Laura Walker, a confer a degree upon observer in the Scripps Research Kellogg School of Science and Technology, added, “This hypervariable loop (CDR3) that forms the modern subdomain is too unusually long in the place of every antibody. Almost all of the antibodies we be sure to exist broadly neutralizing in countervail to HIV have one unusual feature or some other.”

Pejchal notes that the studious mood also revealed that PG16 was sulfated, suggesting possible mechanisms of action not usually seen in antibodies this effective against HIV.

While the scientists were unsuccessful to such a degree far in crystallizing PG16’sitting sister molecule PG9, they were efficient to pick up insight into its action from biochemical studies using both molecules. By switching a small (seven-amino pricking) part of the CDR3 subdomain of PG9 for a similar part from PG16, the team changed the subset of HIV isolates neutralized by the antibody. This confirmed the loop in act of asking was the “business end” of the antibody and suggested that it might be possible to create other interesting variants of the antibody by manipulating this locality.

Seth Berkley, president and CEO of IAVI, that funded the study by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institute of Health (NIH), noted, “These studies of PG16 have taught us a lot about how these neutralizing antibodies be. I am particularly excited by the possibilities these tools and materials open up for AIDS vaccine disentanglement, since the width and strength of HIV neutralization achieved by the agency of PG16 is which we’issue taste to see in the antibodies elicited by the agency of a vaccine. IAVI and its researchers will continue to defend the application of these tools and materials to the design of new immunogens for HIV. We confidence that we will be accomplished to remove the insights gleaned from this revolve in the mind into the design of a promising AIDS vaccine aspirant.”

In addition to Wilson, Burton, Pejchal, and Walker, authors of the notes, “Crystal make and functional studies of broadly reactive antibody PG16 reveal a fresh H3 subdomain that mediates potent neutralization of HIV-1,” are Robyn Stanfield and Pascal Poignard of Scripps Research and IAVI, Wayne Koff and Sanjay Phogat of IAVI New York. This study was supported by IAVI, NIAID, the Skaggs Institute of the Scripps Research Institute, and the Ragon Institute.

Keith McKeown
Scripps Research Institute

June 02 2010 04:25 am | Immune System

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