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Posted: 12/16/2011
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Ragon Institute Uncovering New Ways the Human Immune System Fights HIV

More than 1.8 million people die of HIV-related causes each year—approximately 5,000 deaths per day.* HIV is a particularly significant threat in the sub-Saharan region of Africa. In some areas, the occurrence of HIV is eight times higher for women than men; an estimated one in three women seeking care during pregnancy is HIV positive. By age 35, the infection rate for men rivals that of women in the region. Researchers in South Africa and Boston are working with Microsoft Research to fight HIV.

Seeking Solutions in Africa
Today, the primary resource for combatting the human immunodeficiency virus (HIV) epidemic is prevention in the form of educational outreach. In many places, free antiretroviral (AVR) therapy is now available for HIV-positive persons, but the need for lifelong therapy, together with new cases, will be a growing challenge for even the most robust economies. Barring the discovery of a cure, the best way to slow—and potentially reverse—the progress of the epidemic is to vastly reduce the volume of new cases through vaccination.

A number of HIV vaccines are in various stages of development. A notable multiorganizational effort is laying the groundwork for testing future HIV vaccine candidates in Durban, South Africa—the location was selected due to the high rate of HIV infection in this area. The effort is led by Bruce Walker, Director of the Ragon Institute at Massachusetts General Hospital (MGH), MIT, and Harvard, and a Professor of Medicine at Harvard Medical School and the University of KwaZulu-Natal, together with South African collaborators who have been involved in these efforts since the beginning.

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* There’s this tremendous amount of diversity among HIV strains, and we’re trying to understand what the constraints on evolution are, what the virus can be, and how the virus tries to change itself in order to avoid the immune system. *

Bruce Walker, MD
Director, Ragon Institute at MGH, MIT, and Harvard; Professor of Medicine, University of KwaZulu-Natal

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The team has been able to recruit large numbers of people who are HIV-positive to help with this project. “With our South African collaborators, we spent the last decade building up an infrastructure here that allows us to do studies of the body’s defense mechanisms in the laboratory from blood specimens from these patients that will give us insights we otherwise would never get if we had to freeze down samples and ship them back to the United States,” Walker explains. “Together with our South African collaborators, we’ve put a lot of effort into creating an environment here that allows us not only to do studies in people quite effectively in a high-incidence area, but also allows us to do the research that has to accompany that.”

Joining Walker and the Ragon Institute in this effort are the Centre for the AIDS Programme of Research in South Africa (CAPRISA) and the KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH). Microsoft Research is working with the Ragon Institute to quantify how the immune system attacks various fragments of HIV—data that will, hopefully, lead to a vaccine.

Innovative Research Methods
The Ragon Institute was established to engage professionals from a variety of disciplines to develop innovative approaches to research. For the HIV research project, the Ragon team assembled representatives of the life sciences, engineering, and even the business community.

“Our feeling (at Ragon) is that the full scientific toolbox has never been applied to the problem, and that by bringing people from diverse fields into the HIV field, we’ll be able to apply technologies that could actually answer important questions—technologies that are there right now but haven’t been utilized,” explains Walker. “There’s this tremendous amount of diversity among HIV strains, and we’re trying to understand what the constraints on evolution are, what the virus can be, and how the virus tries to change itself in order to avoid the immune system.”

Ragon’s unique approach has led to some breakthroughs. For example, the team took a theory that is traditionally used to study stock market fluctuations and applied it to the evolution of HIV. By using this theory, the team increased their understanding of how HIV mutates to evade detection by the body’s immune system. Researchers also identified vulnerable regions of HIV that can be effectively targeted by the immune response. This information will be used to investigate ways to compel the immune system to target the most vulnerable regions of the virus, thus driving the virus into extinction.

Fighting HIV with Data
The team has amassed vast amounts of data since the beginning of the research project, but Walker and his team were challenged with how to analyze and parse such a large quantity of data so that they could apply it to their research. Microsoft Research had been seeking a high-impact project in the biosciences that would help a lot of people if it proved successful, and Walker’s HIV research project needed the kind of help that Microsoft Research could provide.

“When we first met Bruce, he had a very tricky problem to analyze,” remembers David Heckerman, Distinguished Scientist and Manager of the eScience group at Microsoft Research. “He had this great data set but he didn’t know how to analyze it. We happened to have just the right algorithm for it and this large bank of computers at Microsoft that could do this massive amount of computation. He gave us the problem on Friday. On Monday, we had a completed analysis for him.”

Microsoft Research is working with the Ragon Institute to analyze data sent from the Ragon team in Africa in order to quantify how the immune system attacks various fragments of HIV. The collaboration between the Ragon teams in Boston and South Africa, CAPRISA, and K-RITH is very fluid, Heckerman says. The teams in South Africa are constantly sending new data sets to Microsoft Research for analysis. Walker and his team have gathered data, including samples of HIV when it is infecting a particular individual. Microsoft Research analyzes the data and identifies interesting relationships within the data. 

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“One of the biggest challenges in building a vaccine for HIV is that HIV mutates a lot,” Heckerman notes. Heckerman explains that every time HIV copies itself, it creates a new mutation that can potentially evade the immune system. To get a perspective on the severity of the HIV mutations, the number of mutations of HIV in a single individual who has contracted the virus is comparable to all of the mutations that have ever occurred in the influenza virus—the virus that causes the flu. Researchers have been struggling for years to develop a flu vaccine that overcomes flu variability such that it can be used every year; imagine how difficult it is to create a vaccine for HIV.

While the virus has a strong evolutionary advantage—its ability to mutate—the team believes it also has a vulnerability or “Achilles heel”: the presence of certain amino acids that can’t mutate lest the virus will cease to function. Heckerman explains, “We think there are certain fragments of HIV that, when attacked by our immune system, will cause the virus to become sick and die. What we’re doing is cataloguing these fragments of HIV that are vulnerable to attack by the immune system. Then, the plan is to build a vaccine to train our immune systems to attack just those places and ignore all the other places that are a waste of time.”

To catalog the vulnerable fragments of HIV, Microsoft Research is taking data from many individuals in South Africa and correlating that data with how the patient’s body is reacting to the virus, noting whether it is controlling HIV or if the virus is continuing to copy itself and survive.

The team must sort through the different mutations of HIV to see how the immune system attacks the virus and how HIV mutates in response. It is a daunting task; there are millions of possible combinations to sort through. It would take years to process the volume of data that the team receives on a single computer, but Microsoft Research is devoting thousands of computers to this task. We are using an algorithm developed at Microsoft Research called PhyloD. Combined, our hardware and software can complete the analysis in just hours—a critical advantage in the fight against HIV.

“By using the kinds of algorithms that David has developed, we can then look at more precisely defining the vulnerabilities of the virus and defining how to target a vaccine to do what ultimately needs to be done, which is to corner the virus so that it can’t escape,” explains Walker. “There’s a tremendous amount that can be learned by the way the virus changes in response to being poked in different ways. That is such a complex process that it’s not something that you or I could figure out with our own brains. This is something that takes massive computing power, and that’s what David has been able to apply to this.”

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* [Bruce] had this great data set but he didn’t know how to analyze it. We happened to have just the right algorithm for it and this large bank of computers at Microsoft that could do this massive amount of computation. He gave us the problem on Friday. On Monday, we had a completed analysis for him. *

David Heckerman
Distinguished Scientist and Manager, eScience Group, Microsoft Research

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“Our immune system is very broad and complex,” Heckerman notes. “For many years, we’ve known that our immune system produces antibodies and our immune system produces white blood cells, both of which can attack a virus. But recently, working with Marcus Altfeld, Director of the Innate Immunity Program at the Ragon Institute of MGH, MIT, and Harvard, we’ve discovered that there’s another component of our immune system that’s also attacking HIV.” The team recently realized that these immune cells, called natural killer cells, are playing a direct role in helping the body fight HIV.

The Human Face of HIV
Beyond the science and computations lies the reason a vaccine is so desperately needed: preventing further loss of life. Individuals who don’t die as a result of the virus are likely to suffer the loss of a “normal” life, asserts Zinhle Thabethe, Deputy Director for iTEACH in South Africa. She speaks from experience. Thabethe was diagnosed as HIV positive in 2001 at the age of 24. She began AVR therapy through a privately funded clinic a year later. Since beginning AVR therapy, her life has been dominated by the medications—remembering to take them, watching out for side effects, and dealing with the emotional stress of being infected with HIV.

“Taking pills for HIV is really a challenge,” Thabethe observes. “It is doable with a very positive mindset. But you can imagine every day at 6:00, or whatever time a patient chooses, you have to remember to take this particular thing. It’s not like food, where you can eat whenever you’re hungry. With antiretrovirals, it has to be precisely on time. You just cannot miss any tablets, irrespective of what you’re doing. Your life is actually revolving around remembering that you have to take those pills, because they are the reason why you live.”

The precision required by AVR therapy is a dominant factor in the life of any HIV-positive individual. For Purity, a 30-year-old resident of KwaZulu Natal, it is a constant struggle. “Early in the morning at 8:00, I take Tenofovir and Lamivudine. After I eat my breakfast, I take Bactrim and vitamins. In the evening, at 8:00, I take Stocrin (Efavirenz) and Lamivudine.”

Purity does not know exactly when she contracted HIV. She knew she was ill, and sought treatment at the hospital. She was diagnosed with tuberculosis and then, soon after, HIV. “I thought my life was over,” she remembers. “People told us that if you are HIV positive, you’re dead—you’re not going to live. But there is always hope. There is always a way. And I’m here today. I’m fine.”

Purity and Thabethe naturally share a hope that a cure for HIV will be found in their lifetimes. They also hope that a vaccine will be developed to prevent others from contracting HIV and suffering from the physical, mental, and emotional pain that HIV has inflicted upon them. However, until that time, they relay messages of hope to others who contract the virus. Thabethe notes that she has found strength in friends and family who provide a crucial support system, ranging from mental support to delivering her medications to choir practice if she forgets them at home.

Purity has also turned to her family for support, but offers an even greater message of hope for those who are HIV positive: “If I met somebody [who was] HIV positive, I would tell them to hold on. They are still alive. There’s hope,” she says. “They must dream, because that’s what keeps me going. Dreams—dreams and hopes. Because if you don’t have hope and dreams, you see yourself as good as dead.”

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Applied Science

The HIV research being conducted as part of this vaccine project has the potential to help millions through the prevention and treatment of HIV and, perhaps one day, a cure. But it goes beyond just HIV, Walker notes. “Everything we learn studying HIV tells us how the immune system works and how it fails. I want people to understand that the immune system, on a daily basis, is not just protecting us against infections; it’s also protecting us against cancers. Everything we learn here is going to be applicable not just to HIV but to breast cancer and prostate cancer—and will ultimately change the way medicine is practiced. Because our ultimate goal is that we will learn how to harness the immune system to do a better job at what it was initially designed to do.”

*World Health Organization, www.who.int/hiv/data/en/

Websites:
www.ragoninstitute.org/index.html
https://fogartyscholars.org/sites/south-africa-caprisa
www.k-rith.org
http://research.microsoft.com/en-us/collaboration/focus/health/

Resources:
On World AIDS Day, HIV Research Provides a Ray of Hope
Uncovering New Ways the Human Immune System Fights HIV
Arming the Immune System Against HIV
Understanding the Immune Response to HIV
Health and Wellbeing at Microsoft Research Connections
Ragon Institute of MGH, MIT, and Harvard
Centre for the AIDS Programme of Research in South Africa (CAPRISA)
KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH)

Videos:
HIV Research: Seeking Solutions in Africa
HIV Research: The Human Face of HIV

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