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April, 2013

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.

April, 2013

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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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    2013 SEIF Awards Support Researchers in Software Engineering

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    Software engineering tag cloud

    Each year, the Software Engineering Innovation Foundation (SEIF) awards US$25,000 grants to support academic research in software engineering technologies, tools, practices, and teaching methods. SEIF is supported by Microsoft Research Connections Computer Science in conjunction with the Research in Software Engineering Group (RiSE). This year, we were joined by the Microsoft Technology Policy Group.

    SEIF supports fundamental and applied research. As Tom Ball, research manager in the RiSE Group at Microsoft Research Redmond says: “SEIF is based on the premise that solid software engineering foundations are fundamental to every kind of system Microsoft builds, so software engineering makes a good base from which attract a wide variety of research in hot topic areas and to partner with academics and groups inside Microsoft Research.” Accordingly, the SEIF 2013 Request for Proposals added device and cloud computing and natural user interface (NUI) based applications to ensure a more comprehensive representation of digital technologies.

    The 2013 SEIF Awards included some fascinating projects, such as:

    • CheckCell: Data Debugging for Spreadsheets
      Emery Berger, University of Massachusetts Amherst, United States 
    • Understanding Parallelism and Automating Refactoring for Readability and Performance
      Danny Dig, University of Illinois at Urbana-Champaign, United States 
    • Mobile/Social Debugging Games for Computing Education
      Andrew J. Ko, University of Washington, United States
    • Engineering Integrity and Confidentiality for the STAR-Vote Electronic Voting System
      Dan S. Wallach, Rice University, United States

    NUI applications facilitate human-computer interaction (HCI) by providing more natural forms of input such as gesture, voice, context, anticipatory processing based on a user’s past actions, and environmental awareness. The goal of NUI applications is to provide more intuitive and sophisticated forms of input that are adaptive to the user and require minimal user training—in particular, for the aging population, people with disabilities, socially or geographically isolated individuals, and underserved populations—to promote digital inclusion where other interfaces, such as keyboard and mouse, are impractical.

    Additionally, with the advent of new tablet devices and ever more powerful phones, applications that use software services and cloud computing become both challenging and rewarding areas for researchers to explore.

    Four of this year’s SEIF awards support this area of scientific exploration:

    • Nilanjan Banerjee at University of Maryland, Baltimore County, is constructing a wearable assistive device that recognizes gestures for paralysis patients.
    • Eelke Folmer at University of Nevada, Reno, is creating a spatial navigator for people who are blind.
    • Gillian R. Hayes at University of California, Irvine, is building interactive surfaces with body-based interactions to provide guidance to children with autism spectrum disorder (ASD).
    • Shaun K. Kane and Amy Hurst at University of Maryland, Baltimore County, will work on Wheeltop Interaction: Full-Body Gesture Control for Power Wheelchair Users

    These are just some highlights from the 16 innovative software engineering projects recognized by this year’s awards, now in their fourth year. You can read more about them and the rest of the SEIF winners on the SEIF website.
    Congratulations to the winners of the 2013 SEIF awards!

    Judith Bishop, Director of Computer Science, Microsoft Research Connections

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