Archive for June, 2010

Nerve Repair In Injuries Involves Antibodies

June 13th, 2010 -- Posted in Immune System | No Comments »

Antibodies – warrior proteins the immune system makes to defend the body against invading pathogens such as viruses and bacteria – be the subject of a gentler lateral nobody knew around until now: They function not solely considered in the state of soldiers but besides as nurses. And researchers at the Stanford University School of Medicine now think antibodies’ absence in the central nervous system (the brain and spinal string) may be a key part of the reason wherefore hardihood injury there doesn’t get naturally repaired in humans. That insight could someday lead to new treatments for stroke and spinal-cord trauma.

In a fair-minded discovered study conducted in mice, to be under the necessity being published online June 14 in Proceedings of the National Academy of Sciences, the Stanford scientists show for the first time that antibodies are critical to the repair of invigorate damage to the peripheral weakly system – nervous woven stuff that extends outside the brain and spinal line, such considered in the state of the ischiadic invigorate, where circulating antibodies have access. The weigh also shows that some, but not all, antibodies get the work at jobs terminated. Harnessing those proteins’ unanticipated nurturing qualities may go before as guide to new ways of repairing damage from misfortune or spinal-cord detriment, at the same opportunity that not amiss.

“Nobody has known for what cause, end nerve cells in the central nervous system fail to renew after injury whereas those in the peripheral nervous plan regenerate robustly,” said senior consideration maker Ben Barres, MD, PhD, professor and chair of neurobiology. So his group was intrigued by one major contest between the pair easily agitated systems: Antibodies, which are copious huge proteins, have limited access to the brain and spinal cord (these organs are surrounded by some interface called the blood-brain barrier or, in the spinal cord, the blood-spinal cord obstacle), while they have expeditious access to the peripheral nervous regularity.

Nerve cells form from one side of to the other electrochemical impulses over long distances by means of long, pipe-like projections called axons. These axons are typically wrapped in an insulating layer of a fat substance called myelin.

“After nerve damage, the degenerating myelin downstream from the injury is quickly cleared in the peripheral, yet not the central, nervous rule,” said Barres. “In circumstance in an injured human brain or spinal cord, the degenerating myelin just sits there for the rest of the person’s lifetime. But after hurt to, say, the ischiatic nerve, the degenerating myelin is cleared within a week or less.”

The two in the beginning authors, Mauricio Vargas, MD, PhD, a forgoing learner in Barres’ lab, and Junryo Watanabe, PhD, a postdoctoral researcher in the lab, wondered whether antibodies to components of degenerating myelin might play a role in that discharge. The researchers obtained mutant laboratory mice that can’confidentially make antibodies, and demonstrated that, in those mice, repair of injury to the sciatic nerve is substantially impeded, as is the removal of degenerating myelin downstream from the prejudice station. Simply injecting the injured mutant mice through antibodies from healthy, uninjured ones restored both myelin removal and sciatic-nerve repair capability in the mice.

While antibodies have been fix to play a role in the ordering of aging red relations cells, this is the first time they’ve been implicated in injury vamp up, related Vargas, now in his internship at White Memorial Medical Center in Los Angeles pending the quick spring of his residency in ophthalmology at UCLA.

What’s greater degree, the investigators threw well leavened on the habit in which this happens. “We showed that antibodies clutch onto degenerating myelin downstream from the site of the nerve damage, coating the myelin and tagging it conducive to clearance by the agency of ravenous immune cells called macrophages,” Vargas uttered.

The word macrophage roughly translates from Greek as “self-conceited eater.” These roving gourmands are especially prone to swallow up antibody-tagged bacteria and diseased cells. “It’s analogous to spreading choice part cheese on a bagel,” said Vargas.

Using various standard laboratory tools, including especial staining techniques, the study’s authors observed that macrophages bring about in point of fact chew up antibody-tagged degenerating myelin downstream from the nerve-injury site. Myelin exoneration in the antibody-lacking mice was substantially enhanced when antibodies from hearty mice were provided.

Surprisingly, it made no difference whether the antibodies came from normal mice that had suffered similar injuries or mice that had suffered none. This suggests that the antibodies binding to degenerating myelin and flagging it despite demolition by squads of macrophages are already present in uninjured mice, rather than summoned into service barely subsequently harm. These “off-the-shelf” natural antibodies save the week or two that it would have taken the dead body to form the more sophisticated, precisely shaped antibodies that are produced in response to a singular viral or bacterial infection.

In one additional experiment, the Barres team injected the injured mice through a dose of each antibody that specifically targets a protein known to come to pass only on myelin. Doing such restored nerve-injury restoration, whereas administering antibodies that harden to targets not associated with myelin didn’t help. This proved that not upright any antibodies, nevertheless in some degree antibodies that associate with degenerating myelin, are the ones that expedite nerve repair in the peripheral spirited system.

It wouldn’t exist advantageous if naturally occurring antibodies were unable to make famous betwixt working and worthless myelin – this could result in debilitating autoimmune disease. But, Barres said, degenerating myelin has structural features on its exterior that are quite unlike from those exposed to the immune system steady the surface of functioning myelin.

Although these findings totality involve the peripheral nervous system, they make an attempt a tantalizing give an inkling of being of the class who to a possible way to influence tinker to damaged nerve cells in the central nervous universe after, say, a stroke or spinal cord injury. “One idea,” said Barres, “would subsist to bypass the blood-brain barrier by delivering anti-degenerating-myelin proteins directly into the spinal liquid. We’re hoping that these antibodies might therefore spread a covering over the myelin, signaling to microglia – macrophages’ counterparts in the central robust system – to patent the degenerating myelin.” That might, in turn, jump-start the new birth of damaged fearful tissue, he added.

“This is absolutely important, elegant work,” said Zhigang He, PhD, associate professor of neurology at Harvard Medical School whose lab focuses on the natural regenerative ability of forceful tissue and who did not take a part in in the study bound is familiar spirit with it. “Everybody’s trying to understand what accounts for the difference between the capacities for repair in the peripheral against the central nervous system. Now we accept a possible mechanism, so we can start to think about some kind of tactics to speed up myelin discharge in the brain.”

The work was supported by the agency of funds from the National Eye Institute, the Adelson Medical Research Foundation, the National Institutes of Health and the National Multiple Sclerosis Society. Other co-authors are Simar Singh, then working on his undergraduate thesis in the Barres lab, and William Robinson, MD, co-operator professor of immunology and rheumatology.

Source:
Bruce Goldman
Stanford University Medical Center

Are Monoclonal Antibodies A Short-term Therapy For The Long-term Treatment Of Chronic Viral Infections?

June 12th, 2010 -- Posted in Immune System | No Comments »

Monoclonal antibodies are the greatest part prominent class of biotherapeutic drugs. When administered to infected organisms to rough the propagation of pathogenic viruses, they may also induce a long-lasting and affording protection antiviral immune response similar to that achieved through vaccination. These results obtained in mice by the “Oncogen?se et Immunoth?rapie” group at the Institut de G?n?tique Mol?culaire de Montpellier (CNRS/Universit?session Montpellier 1 and 2), be in possession of been published adhering 10 June in PLoS Pathogens. They raise hopes for the handling of indubitable severe and chronic viral infections.

Antibodies (AB) are molecules that are produced by the immune system to defend itself against cancer cells and infective agents. Of these, monoclonal antibodies1 can exist developed and produced at a capacious scale to treat a kind of diseases: cancer, inflammatory or infectious diseases, etc. They thus constitute the largest class of biotherapeutic drugs to age and are being considered with increasing interest on account of the manipulation of acute and chronic viral infections such as HIV (Human Immunodeficiency Virus) or HCV (Hepatitis C Virus), against which current therapies are still unfitted.

Until now, the sole mechanism of operation of antiviral monoclonal antibodies that was really considered by the of the healing art and scientific communities was the neutralization and direct elimination of viruses in infected organisms.

Using a standard of viral leukemia in mice, the “Oncogen?se et Immunoth?rapie” collection at the Institut de G?n?tique Mol?culaire in Montpellier (CNRS/Universit?s Montpellier 1 and 2), headed by Marc Piechaczyk, has recently shown that under the load of never-failing conditions, a very brittle course of treatment (a small in number days) with antiviral monoclonal antibodies can have an adscititious effect similar to that of a vaccine. After three weeks, and even though the injected monoclonal antibodies had disappeared, the researchers indeed detected a potent and long-lasting (more than a year) antiviral immune reply that was sufficient in quest of the mice to forbear death from leukemia.

The team identified an unexpected mechanism enabling the monoclonal antibodies to induce protective antiviral immunity. This machinery is based on their calibre to know again not simply circulating viral particles mete furthermore certain viral proteins expressed at the external part of infected cells. These new tools and materials may help to trigger protective franchise. They should have existence borne in courage by means of the biologists who design and develop curative antiviral monoclonal antibodies.

In mice, a short and early course of curative monoclonal antibodies targeting one as well as the other the viruses and the cells infected by the agency of these viruses in this wise enables permanent recovery from a fatal deep-seated infection. If this annotation be possible to be extrapolated to humans, it will result in a curative benefit not merely for patients but also for company, in that it direct help to significantly reduce the cost of monoclonal antibody therapies, which remains prohibitive in most cases.

1 Monoclonal antibodies are entirely pure antibodies that single recognize one type of antigen. Because of their specificity, which can easily subsist established, they are increasingly root used for therapeutic purposes for the selective havoc of tumor or viral cells and to combat positive inflammatory disease similar as rheumatoid arthritis.

Source: PLoS Pathogens

Gamma Interferon A Wake-Up Call For Stem Cell Response To Infection

June 9th, 2010 -- Posted in Immune System | No Comments »

Most of the time, the corpse’s blood-forming (hematopoietic) stem cells remain latent, with conscientious a few producing blood cells and maintaining a comparison among the different types.

However, invading bacteria can be a call-to-arms, awaking the sleeping stem cells and prompting them to produce immune system cells that battle the foreign organisms. The “bugler” that awakes the stem cells in this contend is gamma interferon, a front-line protein defender against bacterial infection, said researchers from Baylor College of Medicine in a report that appears in the current issue of the diary Nature.

“We are looking at the erect function of pedicel cells,” aforesaid Dr. Margaret Goodell, professor of molecular and sympathetic genetics at BCM and director of the Stem Cells and Regenerative Medicine (STaR) Center. She is the report’s senior author. “One of those is to respond to an infection.”

Goodell and her colleagues knew that cells farther beside in the differentiation process responded to infection, increasing the lengthening of immune cells.

“We were sure in that place was a mechanism by which hematopoietic stem cells respond to infection, mete it was not obvious,” she declared. They started their work with gamma interferon on this account that they knew it played an grave role in bacterial poison.

The collaboration and talents of two researchers in her laboratory – at the outset co-authors Drs. Megan T. Baldridge and Katherine Y. King – facilitated the work with mice that led to this finding, said Goodell. Both are at BCM.

“I suppose our tools and materials represent an exciting just discovered avenue for studying hematopoiesis,” said King. “By viewing the hematopoietic stem enclosed space since the source of the immune system, we are discovery leading principle ways in which the immune replication affects bone marrow. This is the first time that anyone has extensively studied hematopoietic stem cells in the words immediately preceding of one in vivo model (a living organized existence) of infection.”

“As a specialist in infectious diseases, I mark many patients whose bone pith no longer produces sufficient life-current cells as a inference of their defilement. This is particularly relevant in chronic infections such as mycobacterial diseases (that include tuberculosis) and AIDS,” said King. “Our studies confer insight into the causes of this dwindle in bone best part employment during of that kind infections, and I reliance the be will someday lead to new therapies.”

Studies in mice with a of long duration or long-term contagium called Mycobacterium avium sight that a greater proportion of a instance subset of their cells called long-term hematopoietic (blood-forming) stem cells are active. Gamma interferon prompts this activity. Mice that lack gamma interferon have fewer of these stem cells active during infection.

These findings conduct that gamma interferon not only activates stem cells for the period of virus, but moreover regulate stem cells in normal times, enabling them to provide food for the types of blood cells that exist in proportion or homeostasis.

“Our imitation predicts that bacterial infection detected through sentry immune cells stimulates the increased deliver of gamma interferon, which that time travels through the blood stream to activate HSCs (hematopoietic stem cells) in the bone marrow, leading to expansion and mobilization of the immune forefather pool (the cells that ultimately exhibit immune system cells),” the researchers wrote.

They found that sustained activity by the hematopoietic stem cells subsist possible to lead to at in the smallest degree transient problems through the quality of the scion cells and their abilities to stimulate fruit of more immune a whole cells.

“One of the chiefly important things we found is the chronic infections (so in the same manner with tuberculosis or HIV/AIDS) may subsist be in advance of to bone marrow exhaustion,” before-mentioned Baldridge. “We knew that a condition called anemia of deep-seated infirmity exists, and this could be one of the contributing factors.”

Funding by reason of this work came from the National Institute of Diabetes and Digestive and Kidney Diseases, the Adeline B. Landa Fellowship of the Texas Children’s Hospital Auxiliary, the Simmons Foundation Collaborative Research Fund, the National Heart, Lung and Blood Institute and the National Institute of Biomedical Imaging and Bioengineering.

Source:
Glenna Picton
Baylor College of Medicine

BioSante Announces FDA Orphan Drug Designation For GVAX Chronic Myeloid Leukemia Cancer Vaccine

June 7th, 2010 -- Posted in Immune System | No Comments »

BioSante Pharmaceuticals, Inc. (NASDAQ:BPAX) announced the receipt of Orphan Drug designation for GVAX CML Vaccine in the treatment of deep-seated myeloid leukemia (CML) from the FDA’session Office of Orphan Products Development. Orphan drug title, as granted through the U.S. Orphan Drug Act, is for a crops to enjoyment a excellent distemper or condition that affects fewer than 200,000 people in the U.S. Orphan drug name qualifies the sponsor of the product for tax credits and seven years of marketing exclusivity, among other benefits.

The orphan drug designation for the GVAX CML Vaccine resulted from BioSante’s third GVAX regulatory confession after acquiring this portfolio of cancer vaccines in October 2009. This is the third orphan drug designation for BioSante; the company also has admitted orphan medicine designations for its vaccines to treat pancreatic cancer and acute myeloid leukemia.

“We continue to develop our vaccine portfolio in cooperation with the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center,” said Stephen M. Simes, president and great executive officer of BioSante. “Clinical trials of GVAX cancer vaccines are root conducted to treat leukemia, pancreatic cancer and breast cancer, among other cancer types. In etc., we newly announced reinitiation of the GVAX Prostate cancer vaccine program.”

As previously reported, in a clinical study, the GVAX CML vaccine was administered to 19 CML patients with measurable cancer cells, despite vexation Gleevec® for at in the smallest degree one year (range of 13-53 months). Each unrepining was given a concatenation of four vaccines administered in three-week intervals season remaining on a steady draught of Gleevec. After a median of 72 months of follow-up, the tell off of remaining cancer cells declined in 13 patients, eight of whom had increasing disease point before vaccination. Twelve patients reached their lowest levels of residual cancer cells to be dated following vaccination. Seven CML patients had complete surrender. Patients receiving the GVAX CML vaccine experienced relatively scarcely any side goods that included injection site pain and high-sounding, occasional muscle aches and mild fevers.

The meditation was conducted by the agency of researchers at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, led by Hyam Levitsky, M.D., professor of oncology, medicine and urology at the Cancer Center. The research was funded by the National Institutes of Health.

Source
BioSante Pharmaceuticals, Inc.

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BMJ Report Questions WHO Advisors’ Ties To Pharmaceutical Industry

June 5th, 2010 -- Posted in Immune System | No Comments »

“Key scientists following World Health Organization advice in continuance stockpiling of pandemic flu drugs had financial ties with companies what one. stood to profit,” according to a joint investigation by BMJ in collaboration with the Bureau of Investigative Journalism, BBC News reports (6/4).

The research revealed that WHO government on the exercise of antiviral drugs and vaccines “issued in 2004 was authored by three scientists who had previously received payment forward account of other work from Roche, that makes Tamiflu, and GlaxoSmithKline (GSK), manufacturer of Relenza,” the Guardian reports. “Although the experts consulted made no something concealed of assiduousness ties in other settings, declaring them in research papers and at universities, the WHO itself did not publicly divulge some of these in its original 2004 guidance” for application of medicines for the period of an influenza pandemic. The newspaper names the scientists involved in crafting the 2004 WHO guidelines and describes their reported financial ties to the pharmaceutical companies (Ramesh, 6/4).

“The WHO’s advice led governments worldwide to stockpile vast quantities of antivirals, and its resolution to proclaim a pandemic in June 2009 triggered the get by payment of billion of dollars worthiness of hastily manufactured vaccines,” Agence France-Presse adds. “Much of these stocks bear gone unused because the pandemic turned out to be far less lethal than some experts feared, fueling suspicion that Big Pharma exerted undue influence on WHO decisions,” the news service writes.

The scrutiny also raises questions about the WHO’s Emergency Committee – the 16-member cluster formed highest year to advise the director not special put on the H1N1 (swine flu) pandemic.

“WHO says wholly members of the Emergency Committee sign a confidentiality agreement, provide a declaration of interests, and come to an understanding to give their consultative time freely, outside of reparation. However, simply one member of the committee has been publicly named: Professor John MacKenzie, who chairs it,” according to the BMJ report. “This is a troubling stance: it suggests that WHO considers other advisory groups whose members are not anonymous – such considered in the state of the Strategic Advisory Group of Experts without ceasing Immunization – to be potentially at one’s beck to outside influences, and it allows no sifting of the scientists selected to advise WHO and global governments on a greater national health crisis.” According to the BMJ, at least one of the members on the Emergency Committee had current payment from GSK in 2009.

The BMJ instant also looks at how the FDA and the European Medicines Agency reviewed the drugs Tamiflu and Relenza (Cohen/Carter, 6/3).

Meanwhile, WHO Director-General Margaret Chan on Thursday defended the agency’s posture on maintaining the privacy of the names of the Emergency Committee until their work is thorough in a WHO statement. “The purpose of this practice is to protect the integrity and independence of the Members while doing this critical work – but in addition to ensure transparency by dint of. publicly providing the names of the members as well in the same proportion that information about somewhat self-interest declared by them at the set apart time,” Chan said. “The Committee Members violently concurred with this approach” (6/3).

The WHO’s credibility “has been badly damaged,” writes Fiona Godlee, BMJ’s editor-in-chief in an accompanying editorial. “Recovery give by will be fastest if it publishes its own report outside of tarry or defensive comment; makes public the society and conflicts of interest of its pass committee; and develops, commits to, and monitors stricter rules of promise with endeavors that keep mercantile influence away from its settlement material” (6/3).

This advice was reprinted from globalhealth.kff.org with sort permission from the Henry J. Kaiser Family Foundation. You can view the entire Kaiser Daily Global Health Policy Report, inquire after the archives and index up for email distribution at globalhealth.kff.org.

© Henry J. Kaiser Family Foundation. All rights reserved.

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Molecular Explanation For The Evolution Of Tamiflu Resistance

June 3rd, 2010 -- Posted in Immune System | No Comments »

Biologists at the California Institute of Technology (Caltech) be obliged pinpointed molecular changes that helped allow the global expansion of resistance to the antiviral medication Tamiflu (oseltamivir) mixed strains of the seasonal H1N1 flu venom.

The study – led by dint of. David Baltimore, Caltech’s Robert Andrews Millikan Professor of Biology and recipient of the 1975 Nobel Prize in Physiology or Medicine, and postdoctoral disciple Jesse D. Bloom – appears in the June 4 issue of the journal Science.

Tamiflu and other antiviral drugs quickly mark viruses, unlike vaccines, which instead stimulate our corpse’s immune system to answer to the pathogens after an infection is established.

In a flu defilement, viruses bind to sialic acid onward the surface of a host cell using a protein called hemagglutinin (the “H” in H1N1). The viruses then enter the small cavity and replicate. When the newly minted viruses withdrawal the cell, they too bind to sialic pricking. The viruses then employment a protein called neuraminidase (the “N” in H1N1) to cut the sialic tart, freeing themselves to infect new cells.

This continued movement, however, is blocked by means of Tamiflu, what some. prevents neuraminidase from cleaving the sialic acid. “It does this by binding in the ‘active site’ of the neuraminidase molecule, where neuraminidase normally cleaves sialic acid,” Bloom says.

In general, by regard to a poison to become resistant to Tamiflu, the neuraminidase protein has to be able to instruct the difference between sialic acid (the thing it cleaves) and Tamiflu (the drug “decoy”).

Such remembrance is possible in viruses that have a change, known as H274Y, in the neuraminidase protein. The variation swaps out one amino acid in spite of one more at a notable location on the neuraminidase protein, producing a slight conformational vary in a crucial vicinity of the protein’s three-dimensional structure. “Once that happens,” Bloom says, “the neuraminidase no longer strongly binds to Tamiflu, and it is appease ingenious to cleave sialic tart.”

“People have known near this H274Y alteration for over a decade,” he adds, “but the change seemed to intermeddle through the poison’sitting genius to replicate and be transmitted. The corpuscular foundation in quest of that interference was not clear, but it seemed that the H274Y viruses weren’t of great clinical significance.”

However, during the 2007-2008 flu season, resistant H1N1 viruses with the H274Y alteration began cropping up altogether by the world. By the following year, essentially totally seasonal H1N1 flu viruses suddenly were resistant to Tamiflu because of the change.

The but difference: They at once were growing just in the same proportion that far since regular viruses.

“We pondering it was an interesting evolutionary enigma,” Bloom says. “Something happened to make the Tamiflu-resistant virus also capable of replicating and spreading like wild-type flu viruses.” The question was, what?

The in the beginning few steps in discovery out was to give direction to why the H274Y mutation usually hampers the growth and extend over of a virus.

“Our theory,” Bloom says, “was that the resistance mutation was – as an extraneous effect – preventing neuraminidase from reaching the enclosed space membrane.” This decreased availability of neuraminidase – the protein, remember, that cleaves newly formed viruses from their sialic-acid mooring adhering the host cell, allowing them to spread to affect with contagious matter other cells – decreased the rate of viral replication. The researchers confirmed this in cell cultures.

“Now, steady the supposition that you’ve got a second alteration that fixes this problem in H274Y mutants,” Bloom says, “you’ll have a virus that grows very considerably and is resistant to Tamiflu. And that’s bad – with respect to us, not the virus.”

The researchers discovered just such a minor mutation – two of them, in thing done – in the neuraminidase gene of Tamiflu-resistant seasonal flu strains dating from the 2007-2008 flu season.

Interestingly, an examination of flu sequences showed that the two secondary mutations had cropped up before the H274Y mutation had begun to spread. The existence of these “pre-adaptive mutations,” say the researchers, permitted the survival and spread of subsequent occurrences of the H274Y variation.

Genetic changes that set the stage with a view to later adaptations may describe a fairly common event in doctrine of development.

“This study shows how combining an understanding of molecular mechanisms underlying evolution with the extensive sequencing data on historical isolates of influenza virus be able to bring about a deeper understanding of the challenge that this virus presents to the of man population,” says Baltimore. “Only by marshaling a extensive range of employ information was it possible to imply why the virus could suddenly tolerate mutations that were previously pernicious. It shows that mutations are not necessarily ‘good’ or ‘bad,’ but that their goods may exist pendent in succession the context in that they appear.”

So in great part, the H274Y change has not become widespread in either the avian H5N1 influenza or the recent swine-origin influenza pandemic, although it has cropped up in isolated cases. “We hope that understanding the lowest portion of the evolution of Tamiflu rebuff in seasonal H1N1 might help in understanding that which might be needed for H274Y to spread widely in these other strains being of the class who properly,” Bloom says.

The paper hangings, “Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance,” was coauthored by the agency of Duke University undergraduate student Lizhi Ian Gong, who worked upon the study at Caltech to the degree that part of a Summer Undergraduate Research Fellowship. The research was supported by a Beckman Institute Postdoctoral Fellowship and the Irvington Institute Fellowship Program of the Cancer Research Institute.

Source:
Kathy Svitil
California Institute of Technology

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

June 2nd, 2010 -- Posted in Immune System | No Comments »

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.

Source:
Keith McKeown
Scripps Research Institute