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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
Big data—that buzzword seems to dominate information technology discussions these days. But big data is so much more than a clever catchphrase: it’s a reality that holds enormous potential. We now have the largest and most diversified volume of data in human history. And it’s growing exponentially: approximately 90% of today’s data has been generated within the past two years. The exploding science of big data is changing the IT industry and exerting a powerful impact on everyday life.
But what should big data science be, and where is it headed? These are the fundamental questions that have prompted Tsinghua University and Microsoft Research Asia to work together to establish a pioneering graduate course on Big Data Foundations and Applications. Turing Award winner and Tsinghua professor Andrew Chi-Chih Yao spent more than eight months developing the course, which launched in September 2014.
Turing Award winner and Tsinghua professor Andrew Chi-Chih Yao
Solidifying knowledge through academia-industry cooperation
On October 9, Hsiao-Wuen Hon, managing director of Microsoft Research Asia, delivered the course’s first lecture. Dr. Hon stressed that the importance of big data lies not only in its value in academic research but also in its application to real-world problems, which, he said, is why the academia-industry cooperation represented by the course is so critical.
“One of our purposes in launching this course with Tsinghua is to introduce Microsoft’s ideas to students, to let them get to know us better,” he explained. “Meanwhile, our top professional researchers can deepen their understanding of big data while teaching the students. So the course is not just about enhancing the students’ understanding of big data; it’s also about solidifying the researchers’ knowledge of big data.”
Hsiao-Wuen Hon, managing director of Microsoft Research Asia, delivered the course's first lecture.
Echoing the importance of the industry-academia connection, Professor Yao remarked, “Big data is an epoch-making subject. It has influenced all the other disciplines, including computer science and information technology. We should not only focus on the scientific research. Education development is also a new trend. ”
Leading the forefront of big data science
Wei Chen, a senior researcher at Microsoft Research Asia, has been a visiting professor at Tsinghua University since 2007. He has helped design and launch several entry-level courses at Tsinghua, and he is a strong proponent of the new big data course.
“We certainly don’t expect this course to become a platform for its product promotion. Instead, it is being established to provide students with cutting-edge knowledge, to get them engaged in research and technology development, and to foster their ability to do research and experimentation,” he said.
Wei Chen, senior researcher at Microsoft Research Asia, talks with student.
Professor Chen pointed out that while the course will provide an academic understanding of big data, it will also introduce students to real-life cases of Microsoft big data research and applications. In addition, students will have the opportunity to conduct experiments using Microsoft Azure, the company’s cloud-computing platform. He believes these practical, hands-on components distinguish this class from other big data courses.
Feeding the talent pipeline
Microsoft Research has a long tradition of collaborating with universities and has undertaken several initiatives to nurture the next generation of talented researchers. Since 2002, for instance, Microsoft Research Asia has hosted over 4,000 interns and carried out projects with more than 40 universities and institutes. The new big data course comes directly out of that tradition, and both Microsoft Research and Tsinghua University have high expectations for this collaboration. Professor Yao probably put it best, saying, “I believe this world-class course will give students a comprehensive understanding of big data and its knowledge structure, helping them reach their goals in future jobs and research.”
—Kangping Liu, Senior Research Program Manager, Microsoft Research Asia
Collaboration can be a great catalyst for new ideas. Whether working with colleagues from down the hall or a team from another continent, we have found that working together strengthens our ideas. A prime example is the Barcelona Supercomputing Centre – Microsoft Research Centre in Barcelona, Spain. Microsoft Research Cambridge began collaborating with the Barcelona Supercomputing Center (BSC) in 2006. We formalized the relationship with the establishment of the BSC – Microsoft Research Centre in January 2008. The Centre focuses on the design and interaction of future microprocessors and software for the mobile and desktop market segments.
The BSC – Microsoft Research Centre is home to a talented group of students who are working towards their PhDs and who bring their creativity and enthusiasm to tackle tomorrow’s problems. “I am very happy that the Centre is a model of open research,” said Centre director Mateo Valero. “We share our findings with the community and all of our software and applications are available for download at our website.”
The program has an extremely young team with more than 15 PhD candidates, Valero explained. Leading the student group was Ferad Zyulkyarov, who is at the forefront of Transactional Memory (TM) research. Working under the supervision of Valero, and his colleagues Osman Unsal and Adrián Cristal, Zyulkyarov investigated how this new approach to multi-core programming could make software development much easier for future computer architectures.
Ferad Zyulkyarov defends his thesis in Barcelona
A Different Point of View
Previous TM research had focused on evaluating and improving TM implementations. Zyulkyarov took a unique approach to the problem, looking at it from the programmer’s point of view. As part of his thesis, Zyulkyarov developed one of the first real-world TM applications: a rewrite of the Quake Game Server that replaced traditional memory locks with TM atomic blocks. This makes life much easier for the programmer, potentially transforming multi-core software development for the future.
Zyulkyarov encountered some obstacles during his project. For example, he had to develop a better debugger and profiling support, neither of which existed before he created them. When he reviewed the performance of the core server code, Zyulkyarov could see the potential for TM. There is still some optimization work to be done, but the potential is there.
During the project, Zyulkyarov collaborated closely with Tim Harris, senior researcher, Systems and Networking Group, Microsoft Research Cambridge. Harris is proud of the work Zyulkyarov accomplished during their time together. “It’s great to see Ferad’s work come to fruition,” Harris said. “He’s made substantial contributions to the development of programming tools for using TM, and I hope that we’ll now be able to apply these ideas to other parts of the multi-core challenge.”
The First of Many PhDs from Barcelona
The first of the 15 students to receive his PhD, and now at Intel, Zyulkyarov is just one example of the young talent being fostered through the BSC – Microsoft Research Centre, driving the industry to tackle some of its most challenging problems. “In the five years since we have started, the Centre has matured quite a lot, and this is the first fruit of the collaboration with BSC and Microsoft Research,” Valero said, adding he is especially grateful to Harris for serving as Ferad’s mentor. “I know that more [success stories] will follow soon,” he added.
I am very glad—thinking back to my first visit to BSC five years ago—in seeing how far we came. This is the result of all the energy and enthusiasm we have all put together in the enterprise. This is only the first of a successful series of PhD awards, which we will see taking place in the next few years.
—Fabrizio Gagliardi, Director, Microsoft Research Connections EMEA (Europe, the Middle East, and Africa)