Science Current Events | Science News | Brightsurf.com
 

Study offers new way to discover HIV vaccine targets

March 22, 2013
Ragon Institute researchers develop a method to identify weak points in viral proteins that could be exploited for vaccine development

Decades of research and three large-scale clinical trials have so far failed to yield an effective HIV vaccine, in large part because the virus evolves so rapidly that it can evade any vaccine-induced immune response.

Researchers from the Ragon Institute of MGH, MIT and Harvard University have now developed a new approach to vaccine design that may allow them to cut off those evolutionary escape routes. The researchers have developed and experimentally validated a computational method that can analyze viral protein sequences to determine how well different viral strains can reproduce in the body. That knowledge gives researchers an unprecedented guide for identifying viral vulnerabilities that could be exploited to design successful vaccine targets.

The team, led by Arup Chakraborty, the Robert T. Haslam Professor of Chemical Engineering, Chemistry, Physics and Biological Engineering at MIT, has designed protein fragments (peptides) that would target these weaknesses. Ragon Institute researchers are now developing ways to deliver the peptides so they can be tested in animals.

"We think that, if it continues to be validated against laboratory and clinical data, this method could be quite useful for rational design of the active component of a vaccine for diverse viruses. Furthermore, if delivered properly, the peptides we have designed may be able to mount potent responses against HIV across a population," says Chakraborty, who is also the director of MIT's Institute for Medical Engineering and Science.

Chakraborty and his colleagues describe their findings in the March 21 issue of the journal Immunity. Lead author of the paper is Andrew Ferguson, a former postdoc in Chakraborty's lab who is now an assistant professor at the University of Illinois at Urbana-Champaign. Other authors are Bruce Walker, director of the Ragon Institute and a professor at Harvard Medical School; Thumbi Ndung'u of the Ragon Institute and the Doris Duke Medical Research Institute in South Africa; and Jaclyn Mann and Saleha Omarjee of the Doris Duke Medical Research Institute.

"This work stems from the novel approach to science that is the central mission of the Ragon Institute: to draw researchers from diverse scientific disciplines to catalyze new advances, the ultimate mission being to harness the immune system to prevent and cure human diseases," Walker says.

Rapid evolution

Typically when a vaccine for a disease such as smallpox or polio is given, exposure to viral fragments primes the body's immune system to respond powerfully if it encounters the real virus. With HIV, it appears that when immune cells in a vaccinated person attack viral peptides that they recognize, the virus quickly mutates its protein sequences so immune cells no longer recognize them.

To overcome this, scientists have tried analyzing viral proteins to find amino acids that don't often mutate, which would suggest that they are critical to the virus's survival. However, this approach ignores the fact that mutations elsewhere in the protein can compensate when those seemingly critical amino acids are forced to evolve, Chakraborty says.

The Ragon Institute team focused on defining how the virus's ability to survive depends on the sequences of its proteins, if they have multiple mutations. This knowledge could enable identification of combinations of amino acid mutations that are harmful to the virus. Vaccines that target those amino acids would force the virus to make mutations that weaken it.

With existing HIV protein sequence data as input, the researchers created a computer model that can predict the fitness of any possible sequence, enabling prediction of how specific mutations would affect the virus.

In this paper, the researchers focused on an HIV polyprotein called Gag, which is made up of several proteins that together are 500 amino acids long. The proteins derived from Gag are important structural elements of the virus. For example, a protein called p24 makes up the capsid that surrounds the virus's genetic material.

Each position in HIV proteins can be occupied by one of 20 possible amino acids. Sequence data from thousands of different HIV strains contain information on the likelihood of mutations at each position and each pair of positions, as well as for triplets and larger groups. The researchers then developed a computer model based on spin glass models, originally developed in physics, to translate this information into predictions for the prevalence of any mutant.

Using this model, the researchers can enter any possible sequence of Gag proteins and determine how prevalent it will be. That prevalence correlates with the fitness of a virus carrying that particular protein sequence, a relationship that the researchers demonstrated by using the model to predict the fitness of a few dozen Gag protein sequences, and verified by engineering those sequences into HIV viruses and testing their ability to replicate in cells grown in the lab. They also tested their predictions against human clinical data.

Visualizing fitness

The model also allows the researchers to visualize viral fitness using "fitness landscapes" - topographical maps that show how fit the virus is for different possible amino-acid sequences for the Gag proteins. In these landscapes, each hill represents sequences that are very fit; valleys represent sequences that are not.

Ideally, vaccine-induced immune responses would target viral proteins in such a way that mutant strains that escape the immune response correspond to the fitness valleys. Thus, the virus would either be destroyed by the immune response or forced to mutate to strains that cannot replicate well and are less able to infect more cells.

This would mimic the immune response mounted by people known as "elite controllers," who are exposed to the virus but able to control it without medication. Immune cells in those people target the same peptide sequences that the model predicted would produce the biggest loss of fitness when mutated.

This general approach could also be used to identify vaccine targets for other viruses, Chakraborty says.

"The reason we are excited about this is that we now have a method that combines two technologies that are getting cheaper all the time: sequencing and computation," he says. "We think that if this continues to be validated, it could become a general method of obtaining the fitness landscapes of viruses, allowing you to do rational design of the active components of vaccines."

"This work is a great example of how integrating expertise from different scientific disciplines - in this case physics, computational biology, virology and immunology - can accelerate progress toward an HIV vaccine," Walker says.

Massachusetts Institute of Technology


Related Immune Response Current Events and Immune Response News Articles


New oral drug regimens cure hardest-to-treat hepatitis C
Two new pill-only antiviral drug regimens could provide shorter, more effective treatment options with fewer side effects for the majority of patients infected with hepatitis C, even those most difficult to treat, according to the results of two studies published in The Lancet.

Immune response may cause harm in brain injuries, disorders
Could the body's own immune system play a role in memory impairment and cognitive dysfunction associated with conditions like chronic epilepsy, Alzheimer's dementia and concussions? Cleveland Clinic researchers believe so, based on a study published online by PLOS ONE.

TGen-led study seeks to understand why some HIV-positive men are more infectious than others
A new study led by the Translational Genomics Research Institute (TGen) provides insights into the interplay among bacteria, viruses and the immune system during HIV infection.

Combination antiretroviral therapy helps treat HCV in patients co-infected with HIV
Treatment of HIV patients co-infected with the hepatitis C virus (HCV) with an anti-retroviral drug therapy not only tackles HIV, but also reduces HCV replication, according to a new study lead by a University of Cincinnati researcher.

New view of stomach cancer could hasten better therapies
In a massive effort to catalog the molecular causes of stomach cancer, scientists, including researchers at Dana-Farber Cancer Institute, have identified four subtypes of tumors based on shared mutations and other molecular abnormalities.

Experiments prove
Researchers in Germany and the U.S. have proven for the first time that specific individual cells of the immune system, termed central memory T cells, have all the essential characteristics of adult tissue stem cells. Such cells are capable of perpetuating themselves indefinitely as well as generating diverse offspring that can reconstitute "tissue" function.

New model helps explain how human-provided food resources promote or reduce wildlife disease
Scientists have long known that providing supplemental food for wildlife, or resource provisioning, can sometimes cause more harm than good.

Researchers create vaccine for dust-mite allergies
If you're allergic to dust mites (and chances are you are), help may be on the way.

Potential new flu drugs target immune response, not virus
The seriousness of disease often results from the strength of immune response, rather than with the virus, itself.

Stem cells aid muscle repair and strengthening after resistance exercise
A new study in mice reveals that mesenchymal (mezz-EN-chem-uhl) stem cells (MSCs) help rejuvenate skeletal muscle after resistance exercise.
More Immune Response Current Events and Immune Response News Articles

Immune Response

Immune Response


On the wet Olympic peninsula of Washington state. Physician's Assistant Rick scales is having problems with some of his terminally-ill patients– –they aren't dying … Along with Makah tribal cop Jasmine Hughes, Scales starts to poke around, and they find way more than they expected. A classic medical mystery, from New York Times Bestselling author Steve Perry.

Primer to The Immune Response, Second Edition

Primer to The Immune Response, Second Edition
by Tak W. Mak (Author), Mary E. Saunders (Author), Bradley D. Jett (Author)


Written in the same engaging conversational style as the acclaimed first edition, Primer to The Immune Response, 2nd Edition is a fully updated and invaluable resource for college and university students in life sciences, medicine and other health professions who need a concise but comprehensive introduction to immunology. The authors bring clarity and readability to their audience, offering a complete survey of the most fundamental concepts in basic and clinical immunology while conveying the subject's fascinating appeal. The content of this new edition has been completely updated to include current information on all aspects of basic and clinical immunology. The superbly drawn figures are now in full color, complemented by full color plates throughout the book. The text is further...

Immune response

Immune response
by Richard Helfrich (Author), James Cordell (Author)


179 pages

The Immune Response to Infection

The Immune Response to Infection
by Stefan H. E. Kaufmann (Editor), Barry T. Rouse (Editor), David L. Sacks (Editor)


Examines the mechanisms of both the innate and adaptive immune systems as they relate to infection and disease. Explores the underlying mechanisms of immunity and the many sequelae of host-pathogen interactions, ranging from the sterile eradication of the invader, to controlled chronic infection, to pathologic corollaries of the host-pathogen crosstalk. Discusses the pathogenesis of certain autoimmune disorders and cancers that are induced by infectious agents but then become independent of the infection process. Serves as a resource for immunologists, molecular microbiologists, infectious disease clinicians, researchers, and students.

The Immune System Recovery Plan: A Doctor's 4-Step Program to Treat Autoimmune Disease

The Immune System Recovery Plan: A Doctor's 4-Step Program to Treat Autoimmune Disease
by Susan Blum (Author), Mark Hyman (Foreword), Michele Bender (Foreword)


• Are you constantly exhausted?

• Do you frequently feel sick?

• Are you hot when others are cold, or cold when everyone else is warm?

• Do you have trouble thinking clearly, aka “brain fog”?

• Do you often feel irritable?

• Are you experiencing hair loss, dry skin, or unexplained weight fluctuation?

• Do your joints ache or swell but you don’t know why?

• Do you have an overall sense of not feeling your best, but it has been going on so long it’s actually normal to you?

IF you answered yes to any of these questions, you may have an autoimmune disease, and this book is the “medicine” you need. Among the most prevalent forms of chronic illness in this country, autoimmune disease affects...

Bacterial Evasion of Host Immune Responses (Advances in Molecular and Cellular Microbiology)

Bacterial Evasion of Host Immune Responses (Advances in Molecular and Cellular Microbiology)
by Brian Henderson (Editor), Petra C. F. Oyston (Editor)


Over the past fifty years cells and mediators involved in our immune defences have been painstakingly identified. However, it is only relatively recently that the ability of microorganisms to evade immunity has been recognized and investigated. This volume introduces the mechanisms used by bacteria to evade both humoral and cellular immune responses, using systems ranging in complexity from the simple quorum sensing molecules (acyl homoserine lactones) to the supramolecular syringe-like devices of type III secretion systems.

Immune Response and the Eye (Chemical Immunology and Allergy)

Immune Response and the Eye (Chemical Immunology and Allergy)
by Jerry Y. Niederkorn (Editor), Henry J. Kaplan (Editor)


In memory of J. Wayne Streilein, the pioneer in ocular immunology The second edition of Immune >Response and the Eye' highlights recent insights into the >dangerous compromise' between the immune system and the eye, which protects the eye against pathogens while limiting inflammation and immune-mediated injury to ocular tissues with little or no regenerative potential. It discusses the broad spectrum of physiological, immunological, anatomical, and biochemical adaptations that conspire to closely regulate the tone and tenor of immune responses in the eye. This volume further describes immune-mediated diseases that occur when the compromise between the immune system and the eye is breached. This breakdown in immune privilege threatens the vision of millions each year. Finally, recent...

The Immune System

The Immune System
by Peter Parham (Author)


The Immune System, Third Edition emphasizes the human immune system and synthesizes immunological concepts into a comprehensible, up-to-date, and reader-friendly account of how the immune system works.  Written for undergraduate, medical, veterinary, dental, and pharmacy students in immunology courses, it makes generous use of medical examples to illustrate points.  The Third Edition has been extensively revised and updated and includes two new chapters on innate and adaptive immunity, which explore the physical, cellular, and molecular principles underlying these responses to infection.  It also features enhanced coverage of aspects of innate immunity such as the complement system, Toll-like receptors, defensins, and C-reactive protein; the role of dendritic cells in initiating...

Understanding Pathophysiology, 5e (Huether, Understanding Pathophysiology)

Understanding Pathophysiology, 5e (Huether, Understanding Pathophysiology)
by Sue E. Huether RN PhD (Author), Kathryn L. McCance RN PhD (Author)


Learn the essential concepts of pathophysiology and stay up to date on treatments, manifestations, and mechanisms of disease with Understanding Pathophysiology, 5th Edition. Filled with vibrant illustrations and complemented by online resources that bring pathophysiology concepts to life, this easy-to-read text delivers the latest, most accurate information on the disease process across the lifespan, giving you the fundamental knowledge you need to move forward in your nursing education. Consistent presentation helps you better distinguish pathophysiology, clinical manifestations, and evaluation and treatment for each disease.More than 1,000 high-quality illustrations vividly depict clinical manifestations and cellular mechanisms underlying diseases.Lifespan coverage details age-specific...

The Immune System Cure: Optimize Your Immune System in 30 Days-The Natural Way!

The Immune System Cure: Optimize Your Immune System in 30 Days-The Natural Way!
by Lorna Vanderheaghe (Author)


What causes one person to catch a cold or flu and another to avoid it? Why do serious outbreaks of infectious diseases leave some individuals untouched? What allows someone to be incapacitated by allergies? The answer lies within nature itself-our immune system. The Immune System Cure provides simple techniques for supercharging your immune system to resist and prevent disease. Through diet, exercise, stress reduction and nutritional supplements, including plant sterols and sterolins, you can harness the power of your immune system in just 30 days and help it combat: Antibiotic-resistant bacteria Fibromyalgia Allergies Hepatitis C Tuberculosis Cancer Rheumatoid arthritis and other autoimmune diseases Chronic fatigue syndrome and more Now you can maintain a healthy natural resistance to...

© 2014 BrightSurf.com