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Although medical science has made great progress in managing HIV infection through modern drugs, 1.7 million people die of AIDS each year, with a disproportionate number of deaths in developing countries. Even access to life saving drugs cannot cure the disease: patients require lifelong drug maintenance and face the never-ending danger of developing resistance or adverse side effects to the medications.
An HIV vaccine thus remains an utmost public health priority. To this end, studying the mechanisms by which some people are able to naturally control infection offers hope for researchers seeking insights into what constitutes an effective immune response—and how we might design a vaccine to illicit such a response. In the April 5 issue of Science, an investigative team, led by Richard Apps and Mary Carrington of the National Cancer Institute and aided by researchers in the eScience group at Microsoft Research, reported a new finding that sheds light on the protective potential of the human gene HLA-C, an often overlooked player in the adaptive immune response.
Left untreated, the vast majority of HIV-infected individuals will progress to AIDS, marked by the loss of important cells of the immune system and the resulting onset of opportunistic infections. However, the rate of progression varies widely: the virus progresses within weeks in some individuals, while others control the virus and remain AIDS-free for decades.
Epidemiologic studies of HIV control have repeatedly pointed to the importance of the MHC locus, a cluster of genes that encode proteins that the immune system uses to identify cells that have become virally infected. Of these genes, HLA-B has emerged as a dominant player. Its neighbor, HLA-C, has been largely ignored. The reasons for this are varied, including the relatively low cell-surface expression of HLA-C proteins compared to HLA-A and HLA-B, the observation that HIV actively down regulates surface expression of HLA-A and HLA-B but appears to ignore HLA-C, and the problem that HLA-B and HLA-C genes tend to be inherited together, so any positive effects that could be attributed to HLA-C are often assumed to be the result of neighboring HLA-B. The result is a relative dearth of scientific knowledge regarding the role HLA-C plays in controlling HIV.
Recently, several genome wide association studies have been published that report common genetic variants that correlate with natural HIV control. One of the largest such studies, published in Science in 2010 and coauthored by many of the same investigators as the current study, found a number of important variations in MHC, but the most significant signal was immediately adjacent to the HLA-C gene. Several follow-up studies from Dr. Carrington’s group and others have provided circumstantial evidence that this genetic variant is an imperfect marker for variations in the level of HLA-C cell surface expression—that is, the number of HLA-C proteins present on the cell surface. Now, Dr. Carrington has provided epidemiological evidence that HLA-C expression directly correlates with control, while Microsoft Research Distinguished Scientist David Heckerman and I used models of sequence evolution combined with functional immune response data to provide a proposed mechanism and corroborating evidence that HLA-C expression modulates immune and viral responses. Thus, in contrast to HLA-A and HLA-B, it isn’t that individual variants of HLA-C proteins contribute to varying degrees of control (although that could also be the case), but that overall cell-surface quantities of the protein, regardless of variant, are directly correlated with control, rates of immune targeting, and magnitude of evolutionary pressure exerted upon the virus. These findings suggest a broader role for variations in HLA surface expression across a range of diseases. Indeed, in addition to the protective effect of HLA-C expression on HIV, we observed a correlation between HLA-C expression and increased susceptibility to Crohn’s disease, a complex inflammatory bowel disease that may be related to an overly active adaptive immune response.
Although the finding that increased HLA-C expression levels can contribute to both pathogen control and disease susceptibility complicates our understanding of the immune system, it highlights the importance of this long-overlooked protein and may unlock new research into the mechanisms of natural control, providing potential new targets for vaccine design.
Microsoft Research’s involvement in this study is the result of more than seven years of ongoing research in the HIV community. We have forged ongoing collaborations with more than a dozen labs and have developed statistical models of HIV evolution that have:
Our ongoing research develops and uses tools derived from machine learning and applied statistics to move toward the development of an effective HIV vaccine.
—Jonathan Carlson, Researcher, eScience Research Group, Microsoft Research Connections
The Imagine Cup 2011 winners are revealed! The winning projects hail from Bangladesh, Brazil, Denmark, France, Greece, Ireland, Korea, Poland, Romania, and Taiwan. At the awards ceremony, Microsoft announced a new US$3 million grant program to help recipients realize their vision.
Congratulations to all the winners and every participant in this amazing competition! For more information, read the Research at Imagine Cup 2011 blog.
—Stewart Tansley, Senior Research Program Manager, Microsoft Research Connections, and Jim Pinkelman, Senior Director, Microsoft Research Connections
Powerful Research Tools Shared at the American Geophysical Union Fall Meeting
We love our jobs at Microsoft Research, and a big part of that is about how much we love physics and technology. And chocolate. Consider: if you place helium in a (well-made) bag and let it go, there is nothing to prevent it from ascending to the very edge of outer space; a free ride for a small payload using nothing more exotic than a canister of helium available for $39.95 at your local party supply store. The payload in our case is a GPS and a radio built on .NET Gadgeteer (more on this below), the purpose is atmospheric research, and the underlying technology is from Microsoft. This blog is about sharing our technology and tools with Earth scientists at their annual convention in early December in San Francisco.
Microsoft .NET Gadgeteer display at the Microsoft Research exhibit booth
We set up our booth at the American Geophysical Union (AGU) Fall Meeting exhibit hall in San Francisco’s Moscone Center. The exhibit hall is an enormous space where universities, specialized companies, non-profits, and government agencies (such as NASA) were displaying their own exhibits in parallel with the massive intellectual swap meet going on in the poster and lecture rooms—and in the hallways in between. The underlying subject: how does the Earth work and where is our ecosystem headed? This is serious business, and we at Microsoft Research are trying to help get answers by providing support on the technology front.
Exhibits at major scientific meetings are a great way to show scientists some of the powerful tools that are available from Microsoft Research, and so that is what we did, mostly one conversation at a time. One of my favorite aspects of working in an exhibit booth is the look on people’s faces after I’ve shown them some technology we provide for open use and then tell them it’s free: a scientist’s wide-eyed, open-mouthed astonishment is a great reward for years spent building these tools.
“But where do the helium and the chocolate come in?” you might ask, a fair question. We spent a lot of time prior to the AGU Fall Meeting pondering, “What do people respond to?” because we wanted them to have a positive experience at our exhibit. Well, for me, chocolate and toys are good, and happily, our .NET Gadgeteer team sent their lead technologist and jack-of-all-trades Steven Johnston to join us from Great Britain. .NET Gadgeteer is a whole passel of rapid prototyping technology “toys” [think computer plus sensors plus radio—all modular] supported by a free software development toolkit. Steven's backpack was packed with .NET Gadgeteer devices plus a weather balloon; one quick stop at Ghirardelli and another at the local party supply store and we had chocolate for the booth visitors and helium to inflate the weather balloon. We were ready for business. (The balloon stayed safely tethered, though Steven regularly releases them into the atmosphere back home.)
The AGU Fall Meeting ran December 3–7 with more than 22,000 attendees. Our (welcoming!) booth ran four of those days, during which we collected surveys on data challenges, handed out a metric ton of chocolate, and engaged countless stoppers-by with our ensemble of technologies. This growing ensemble today includes .NET Gadgeteer, Layerscape for data visualization, CLEO, DataUp, Bing Maps, FetchClimate, and more. On a whim, we also brought in an ersatz campfire to conjure up fireside chats, and, to our delight, these were a huge success, thanks to our scientist collaborators (and Kris Tolle’s inspiration). Of particular note: Matthew Smith from the Microsoft Research Cambridge Computational Ecology group presented his research on improving Earth models via data integration—work that is vital to understanding and improving how our predictive models show where we are headed in coming decades.
Fireside chats at the Microsoft Research booth were a huge success, thanks to our scientist collaborators.
To cap off the event, Tony Hey, vice president of Microsoft Research Connections, gave a session talk on who we are and how we can help academic researchers. Tony’s presentation brought in lots of additional visitors, almost all of whom came away with a deepened appreciation of Microsoft’s collaborative work with the academic community. To get a sense of some of what we talked about, check out Getting Started with Layerscape and its many links.
—Rob Fatland, Senior Research Program Manager, Microsoft Research Connections