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Microsoft Research Connections Blog

The Microsoft Research Connections blog shares stories of collaborations with computer scientists at academic and scientific institutions to advance technical innovations in computing, as well as related events, scholarships, and fellowships.

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    HLA-C: An Underappreciated Force in HIV Control

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    HLA-C: An Underappreciated Force in HIV ControlAlthough 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

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    Workshop Explores Opportunities in Verified Software

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    Building verifiably reliable and trustworthy software is one of the ultimate objectives of software engineering. With this goal in mind, academics, scientists, and researchers gathered in Shanghai, China, for the second Verified Software Workshop and Summer School. The event, which took place from August 23 to 31, 2012, attracted approximately 250 faculty and student attendees from more than 70 universities and research institutes and nearly a dozen countries across the Asia Pacific region and beyond.

    World-class scientists and researchers—from Asia, Europe, and North America—provided the latest insights into verification theory, practice, and tools.
    World-class scientists and researchers—from Asia, Europe, and North America—provided the latest insights into verification theory, practice, and tools.

    Co-sponsored by Microsoft Research Asia and East China Normal University, the event explored new directions and emerging opportunities in verified software research, with 21 keynote presentations by world-class scientists and researchers—from Asia, Europe, and North America—providing the latest insights into verification theory, practice, and tools. Especially notable among the prominent presenters were the workshop co-chairs: Professor Tony Hoare, the 1980 Turing Award winner and a principal researcher at Microsoft Research Cambridge, who gave the opening speech, titled, “Algebra Unifies Theories of Programming”; and Professor Jifeng He of East China Normal University and a member of the of the Chinese Academy of Sciences, who delivered a keynote on “A Clock-Based Framework for Modeling Hybrid Systems.”

    The event began with a two-day workshop at East China Normal University that included inspiring lectures from technical and academic leaders. A broad and comprehensive workshop, it featured in-depth talks on such topics as detection of concurrency bugs, safe programming of asynchronous interaction, pervasive model checking, analysis and verification of multiple programs, automation of program verification, concurrent software verification, software analytics and its application, and modeling and verification of hybrid systems.

    A five-day summer school of intense training followed the workshop. Students were treated to lectures focusing on the theoretical nature of concurrency and separation logic. One particular highlight was the hybrid systems session, which taught the KeYmaera logical analysis approach in a single day’s time. In addition, a step-by-step tool session provided attendees with valuable hands-on practice and an in-depth learning experience.

    The event was popular with both students and presenters. Summing up the benefits of the event, one student said, “I acquired cutting-edge research and tools in [the] verification software field, and also had the opportunity to exchange my ideas with innovative peers and academic leads from across the world.”

    Capturing the perspective of the experienced researcher, co-chair Tony Hoare praised the event and laid out his goals for such venues, saying, “We hope to expand the opportunities for industrial application of mature academic research, and to encourage the next generation of advanced researchers to continue the pursuit of deep and interesting questions in areas of the software industry.”

    Professor Tony Hoare, the 1980 Turing Award winner and a principal researcher at Microsoft Research Cambridge, gave the opening speech, titled, “Algebra Unifies Theories of Programming."
    Professor Tony Hoare, the 1980 Turing Award winner and a principal researcher at Microsoft Research Cambridge, gave the opening speech, titled, “Algebra Unifies Theories of Programming."

    Co-chair Jifeng He added, “We have achieved a lot in [the] verified software field with everyone’s great effort, but there is always more work to do. With this event, we hoped to not only inspire our young talent but also provide researchers and faculties worldwide with the advantage of exchanging ideas.”

    Lolan Song, the senior director of Microsoft Research Asia, spoke of the company’s objectives in sponsoring such events, observing that “We hold this event in order to advance the state of the art in software and present a great opportunity for academics, researchers, and students in this area to share and exchange ideas. Also, we hope to identify and cultivate worldwide top talent in verified software areas and build up cadres of experienced users to support eventual use of the tools in the industry.” She also expressed the gratitude of Microsoft Research Asia for the assistance and participation of colleagues from Microsoft Research Cambridge, Microsoft Research Redmond, and Microsoft Research India.

    —Kangping Liu, University Relations Manager, Microsoft Research Connections Asia

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    Innovators Wanted

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    I WANT YOU Uncle Sam PosterI WANT YOU…. Anyone who grew up in the United States, as I did, is familiar with the famous World War II recruiting poster of Uncle Sam exhorting young Americans to enlist in the armed forces. (No, I wasn’t alive then, but the poster is an icon.)

    Well, Uncle Sam is calling again, not for men and women under arms, but for recent graduates, top researchers, and great innovators—in short, for creative young people who want to be agents of change in the digital world. On February 5, the White House announced round 2 of the Presidential Innovation Fellows (PIF) program, a unique effort that brings incredibly talented go-getters from the private sector to work for 6 to 12 months with top government innovators to solve challenges of national importance. PIF projects are selected based on their potential to save lives, save taxpayer money, and fuel job growth.

    Presidential Innovation FellowsI am pleased to be working with the Office of Science and Technology Policy Team (OSTP) in helping to announce this second round of Presidential Innovation Fellowships, especially since the program complements my passion—familiar to regular readers of this blog—to grow the number of women and minorities in computing. The inaugural round of 18 Presidential Innovation Fellows worked on five projects and did a fantastic job, but, astonishingly, the group lacked diversity, even though the United States is renowned as a “melting pot” of cultural and ethnic diversity. For round 2, the OSTP wants to do a better job of reaching a diverse audience.

    This second round of the PIF program include nine projects:

    Disaster Response and Recovery: Collaboratively building and “pre-positioning" needed tech tools ahead of future emergencies or natural disasters, in order to mitigate economic damage and save lives.

    MyUSA: Simplifying the process of finding and accessing information and government services that are right for you. Helping US businesses access the information and services that will help them grow, hire US workers, and export to foreign markets.

    RFP-EZ and Innovative Contracting Tools: Making it easier for the US government to do business with small, high-growth tech companies, and enabling the government to buy better, lower-cost tech solutions from the full range of US businesses.

    Cyber-Physical Systems: Working with government and industry to create standards for a new generation of interoperable, dynamic, and efficient “smart systems”—an “industrial Internet”—that combines distributed sensing, control, and data analytics to help grow new high-value US jobs and the economy.

    Open Data Initiatives: Accelerating and expanding efforts to make government information resources more publicly accessible in “computer-readable” form and spurring the use of those data by entrepreneurs as fuel for the creation of new products, services, and jobs.

    MyData Initiatives: Empowering the people of the United States with secure access to their own personal health, energy, and education data.

    Innovation Toolkit: Developing an innovation toolkit that empowers the US federal workforce to respond to national priorities more quickly and more efficiently.

    21st Century Financial Systems: Moving financial accounting systems of US federal agencies out of the era of unwieldy agency-specific implementations to one that favors more nimble, modular, scalable, and cost-effective approaches.

    Development Innovation Ventures: Enabling the US government to identify, test, and scale breakthrough solutions to the world’s toughest problems.

    If you are looking for an opportunity to make a difference, here is a chance to influence millions of lives by thinking outside of the box and building truly innovative solutions. Presidential Innovation Fellows have a unique chance to serve their country and influence change on a truly massive scale. The White House will be accepting applications from February 5 through March 17, looking to put together dynamic, diverse, and innovative project teams that will produce tremendous results for the residents of the United States.

    PIF applicants need not have deep technical programming skills; rather, they require an ability to think creatively, be an agent for change, and to recognize opportunities where technology can solve problems. I am asking all of you in the academic community to reach out to recent graduates and alumni that you believe can influence positive change and envision innovative solutions. And don’t count yourself out, as this could be the sabbatical of a lifetime. If you are interested in learning more and applying, please visit Presidential Innovation Fellows.

    Rane Johnson-Stempson, Education and Scholarly Communication Principal Research Director, Microsoft Research Connections

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