Flexible Funding Helps Ragon Investigators Identify Key Vulnerability in HIV Virus

An illustration of the Human Immunodeficiency Virus (HIV/AIDS) viruses attacking a host cell.

One of the paradoxes in grant-funded research is that it’s often difficult to secure funding to study a disease if you don’t already have experience working on that disease.

This makes it challenging to incorporate different scientific perspectives—such as those provided by engineers and computer scientists—into research on pressing health needs such as HIV, cancer and neurodegenerative disorders.

Yet it is often these outside perspectives, when combined with the insights of experts in the field, that provide crucial insights for diagnosis and treatment.

When the Ragon Institute of MGH, MIT and Harvard was established in 2009 by a $100M philanthropic donation from the foundation of Philip T. (Terry) and Susan M. Ragon, a key objective of the institute was to incorporate these different scientific perspectives into the fight against the HIV epidemic, says Bruce Walker, MD, the Institute’s director.

The flexible funding provided by the Ragons—who recently made a second $200M donation to endow the institute—has helped to make these collaborations possible and contributed to a recent breakthrough identifying a vulnerability in the structure of HIV.

Tracking A Moving Target

One way that the HIV virus avoids detection by immune cells in the body is through mutations that occur as it replicates, Walker explains. This makes it difficult to train immune cells to recognize and destroy the virus via vaccine.  

To overcome this barrier, Ragon investigators conducted a large-scale study of the amino acids that create the structural bonds between HIV proteins.

In collaboration with Arup K. Chakraborty, PhD, the team initially used software that had been designed to find trends in the stock market to identify a small subset of amino acids that were important for the virus to be able to replicate.

The data suggested that certain amino acids, the building blocks of proteins, were particularly important to maintain critical structural elements that the virus required.

Finding this, two postdoctoral fellows, Gaurav Gaiha, MD, PhD and Elizabeth Rossin, MD, PhD set out to  see if they could learn more about HIV’s vulnerability by studying HIV structure directly, applying Network Theory to understand the key bonds among amino acids that are required for structures the virus needs to function effectively.

“You can think about it like a social network,” Walker says. “There are certain individuals where if you take them out of the network the whole thing falls apart. But there are others where it doesn’t matter if they come to the meetings or not, because they don’t influence much.

“The same applies to proteins—there are certain amino acids that are critical to the network, in other words are critical to maintaining key structural elements the virus needs to survive.”

The Ragon team then strengthened their findings by looking at how the immune cells of elite controllers—a small subset of HIV positive individuals who can keep the virus from progressing into AIDS without antiviral drugs—respond to these highly networked amino acids.

They found that the immune cells of elite controllers had a stronger response to those amino acids than non-controllers, which could explain how these patients are able to keep HIV in check without treatment.

Since the highly networked amino acids are less able to mutate, the main path for the virus to escape from immune detection is taken away.

“We are excited because these data support a very credible hypothesis: that we can change the immune system of somebody who is already infected to target highly networked amino acids and get their immune systems to keep HIV in check,” Walker says.

“The same applies for a preventive vaccine, if you can train your immune system to go after the most vulnerable parts of HIV, that’s a really good thing, we think.”

Building for the Future

With the additional funding provided by the Ragons, Walker is extending the institute’s research into other areas of medicine and incorporating more diverse scientific perspectives.

Ragon investigators have started research programs into tuberculosis and influenza and are continuing to study human immunology at the fundamental level to better understand how it works and why it fails in certain circumstances.

“When I look back over the past 10 years, this collaborative approach has created an incredibly exciting place to work,” Walker says. “The flexible funding we’ve had has been enormously catalytic.”

“We live in a scientific environment here with Harvard, Mass General and MIT that is unparalleled,” he adds. “There couldn’t be a better place to make the investment that Terry and Susan have made. We’re enormously grateful for what they’ve done.”

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