Study offers new way to discover HIV vaccine targetsMarch 21, 2013
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.
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.
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 System Articles:
There is a strong correlation between our fear of infection and our skepticism towards immigrants.
The bacterium Salmonella enterica causes gastroenteritis in humans and is one of the leading causes of food-borne infectious diseases.
Monash University (Australia) and Cardiff University (UK) researchers have come a step further in understanding how the human immunodeficiency virus (HIV) evades the immune system.
Eating carbohydrates during intense exercise helps to minimise exercise-induced immune disturbances and can aid the body's recovery, QUT research has found.
By studying a large protein (the C1 protein) with X-rays and electron microscopy, researchers from Aarhus University in Denmark have established a new model for how an important part of the innate immune system is activated.
Dendritic cells represent an important component of the immune system: they recognize and engulf invaders, which subsequently triggers a pathogen-specific immune response.
Researchers have seen, for the very first time, how the human immune system recognizes tuberculosis (TB).
A newly discovered protein from a fungus is able to suppress the innate immune system of plants.
Pathogen epitopes are fragments of bacterial or viral proteins. Nearly a third of all existing human epitopes consist of two different fragments.
Tuberculosis tricks the immune system into attacking the body's lung tissue so the bacteria are allowed to spread to other people, new research from the University of Southampton suggests.
Related Immune System Reading:
How the Immune System Works (The How it Works Series)
by Lauren M. Sompayrac (Author)
How the Immune System Works has helped thousands of students understand what’s in their big, thick, immunology textbooks. In his book, Dr. Sompayrac cuts through the jargon and details to reveal, in simple language, the essence of this complex subject.
In fifteen easy-to-read chapters, featuring the humorous style and engaging analogies developed by Dr. Sompayrac, How the Immune System Works explains how the immune system players work together to protect us from disease – and, most importantly, why they do it this way.
Rigorously updated for this fifth... View Details
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)
One of the most sought-after experts in the field of functional medicine shares her proven four-step program to treat, reverse, and prevent autoimmune conditions and repair your immune system.
• 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... View Details
The Immune System, 4th Edition
by Peter Parham (Author)
The Immune System, Fourth Edition emphasizes the human immune system and presents immunological concepts in a coherent, concise, and contemporary account of how the immune system works. Written for undergraduate, medical, veterinary, dental, and pharmacy students, it makes generous use of medical examples to illustrate points. This classroom-proven textbook offers clear writing, full-color illustrations, and section and chapter summaries that make the book accessible and easily understandable to students.
The Fourth Edition is a major revision that brings the content... View Details
Basic Immunology: Functions and Disorders of the Immune System, 5e
by Abul K. Abbas MBBS (Author), Andrew H. H. Lichtman MD PhD (Author), Shiv Pillai MBBS PhD (Author)
In this updated edition of Basic Immunology, the authors continue to deliver a clear, modern introduction to immunology, making this the obvious choice for today's busy students. Their experience as teachers, course directors, and lecturers helps them to distill the core information required to understand this complex field. Through the use of high-quality illustrations, relevant clinical cases, and concise, focused text, it's a perfectly accessible introduction to the workings of the human immune system, with an emphasis on clinical relevance.... View Details
The Immune System, 3rd Edition
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... View Details
The Immune System
by Peter Parham (Author)
The Immune System, Second Edition has been designed for use in immunology courses for undergraduate, medical, dental, and pharmacy students. This class-tested and successful textbook synthesizes the established facts of immunology into a comprehensible, coherent, and up-to-date account of how the immune system works, rather than presenting immunology as a chronology of experiments and discoveries. Emphasizing the human immune system the text has been designed to break down the barriers which often divide basic and clinical immunology. The reader-friendly text, section and chapter... View Details
The Immune System: A Dewey Decimal novel (Akashic Urban Surreal Series)
by Nathan Larson (Author)
"This final installment of the Dewey Decimal trilogy capably stands alone as a quirky, sparkly read that will embiggen your cerebellum."
"Larson treats the English language as a sort of toy to play with and use for experimentation; language is not just used to tell the story, in other words, but is a part of the story, an extension of its narrator, Dewey Decimal, one of the more offbeat characters in fiction. A fitting conclusion to a unique and memorable trilogy."
"A sharp and satisfying conclusion to one of the... View Details
Immune System: 101 Natural Ways to Boost your Immune System, Fight Germs, and Live a Healthy Life
by Living in Health (Author)
BOOST YOUR IMMUNE SYSTEM! 101 NATURAL WAYS TO BOOST YOUR IMMUNE SYSTEM, FIGHT GERMS, AND LIVE A HEALTHY LIFE Your immune system is the body’s only line of defense against both foreign and internal threats. It is clear therefore that you must maintain your immune system in the best possible condition for optimal health. It is not a myth that some foods are better than others at boosting our immunity. If you were ever wondering what might be the best foods in the world to help keep your immune system in the best shape, then this book is simply the way to go. It really helps to have a great... View Details
The Immune System: A Very Short Introduction (Very Short Introductions)
by Paul Klenerman (Author)
The immune system is central to human health and the focus of much medical research. Growing understanding of the immune system, and especially the creation of immune memory (long lasting protection), which can be harnessed in the design of vaccines, have been major breakthroughs in medicine.
In this Very Short Introduction, Paul Klenerman describes the immune system, and how it works in health and disease. In particular he focuses on the human immune system, considering how it evolved, the basic rules that govern its behavior, and the major health threats where it is... View Details
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... View Details