text:
Study offers new way to discover HIV vaccine targetsMarch 22, 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.
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
Can stress management help save honeybees?
Honeybee populations are clearly under stress--from the parasitic Varroa mite, insecticides, and a host of other factors--but it's been difficult to pinpoint any one of them as the root cause of devastating and unprecedented losses in honeybee hives.
Masking HIV target cells prevents viral transmission in animal model
Cloaking immune cells with antibodies that block T cell trafficking to the gut can substantially reduce the risk of viral transmission in a non-human primate model of HIV infection, scientists report.
Discovery by NUS researchers contributes towards future treatment of multiple sclerosis
A multi-disciplinary research team from the National University of Singapore (NUS) has made a breakthrough discovery of a new type of immune cells that may help in the development of a future treatment for multiple sclerosis (MS).
Immune checkpoint inhibitors may work in brain cancers
New evidence that immune checkpoint inhibitors may work in glioblastoma and brain metastases was presented today by Dr Anna Sophie Berghoff at the ESMO Symposium on Immuno-Oncology 2014 in Geneva, Switzerland.
Pluripotent cells created by nuclear transfer can prompt immune reaction, researchers find
Mouse cells and tissues created through nuclear transfer can be rejected by the body because of a previously unknown immune response to the cell's mitochondria, according to a study in mice by researchers at the Stanford University School of Medicine and colleagues in Germany, England and at MIT.
Every step you take: STING pathway key to tumor immunity
A recently discovered protein complex known as STING plays a crucial role in detecting the presence of tumor cells and promoting an aggressive anti-tumor response by the body's innate immune system, according to two separate studies published in the Nov. 20 issue of the journal Immunity.
Gene therapy provides safe, long-term relief for patients with severe hemophilia B
Gene therapy developed at St. Jude Children's Research Hospital, University College London (UCL) and the Royal Free Hospital has transformed life for men with a severe form of hemophilia B by providing a safe, reliable source of the blood clotting protein Factor IX that has allowed some to adopt a more active lifestyle, researchers reported.
New clue in celiac disease puzzle: Cause of oat toxicity explained
Melbourne researchers have identified why some people with coeliac disease show an immune response after eating oats.
Cell study sheds light on diseases caused by immune system fault
Scientists have discovered how a gene mutation can lead to diseases that occur when the immune system attacks the body by mistake.
Side effects of possible anti-cancer strategy discovered
The Malt1 protein is one of the most important control centers in human immune cells and a real all-rounder.
More Immune Response Current Events and Immune Response News Articles