Jonathan Carlson Archives - Microsoft Research http://approjects.co.za/?big=en-us/research/blog/tag/jonathan-carlson/ Wed, 20 Jul 2016 14:34:39 +0000 en-US hourly 1 https://wordpress.org/?v=6.9.4 HLA-C: An Underappreciated Force in HIV Control http://approjects.co.za/?big=en-us/research/blog/hla-c-an-underappreciated-force-in-hiv-control/ Mon, 08 Apr 2013 09:00:00 +0000 https://blogs.msdn.microsoft.com/msr_er/2013/04/08/hla-c-an-underappreciated-force-in-hiv-control/ 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 […]

The post HLA-C: An Underappreciated Force in HIV Control appeared first on Microsoft Research.

]]> HLA-C: An Underappreciated Force in HIV ControlAlthough medical science has made great progress in managing HIV infection through modern drugs, 1.7 million (opens in new tab) 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 (opens in new tab), an investigative team, led by Richard Apps and Mary Carrington of the National Cancer Institute (opens in new tab) and aided by researchers in the eScience group (opens in new tab) 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 (opens in new tab) 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 (opens in new tab) 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 (opens in new tab), Researcher, eScience Research Group, Microsoft Research Connections

Related Links

The post HLA-C: An Underappreciated Force in HIV Control appeared first on Microsoft Research.

]]> How Microsoft Technology and Research Are Helping Create a Clearer Picture of HIV http://approjects.co.za/?big=en-us/research/blog/how-microsoft-technology-and-research-are-helping-create-a-clearer-picture-of-hiv/ Tue, 14 Dec 2010 13:02:00 +0000 https://blogs.msdn.microsoft.com/msr_er/2010/12/14/how-microsoft-technology-and-research-are-helping-create-a-clearer-picture-of-hiv/ Nearly 30 years since its discovery, the human immunodeficiency virus (HIV) continues to prove a difficult virus to pin down because it mutates so rapidly—a trait which, so far, has made an effective vaccine for this often-deadly condition impossible to develop. That might change, thanks in part to new Microsoft tools that are being used […]

The post How Microsoft Technology and Research Are Helping Create a Clearer Picture of HIV appeared first on Microsoft Research.

]]> Nearly 30 years since its discovery, the human immunodeficiency virus (HIV) continues to prove a difficult virus to pin down because it mutates so rapidly—a trait which, so far, has made an effective vaccine for this often-deadly condition impossible to develop.

That might change, thanks in part to new Microsoft tools that are being used to construct maps of the mutating virus, which may in turn help identify prospective vaccine candidates.

HIV mutates at such a high rate that the virus is distinct for each individual patient. The level of viral variation in one HIV patient is comparable to the worldwide level of variation during the course of an influenza epidemic.

The PhyloD Viewer draws proteins as circles to reveal mutation patterns that could aid in HIV vaccine design.

The PhyloD Viewer draws proteins as circles to reveal mutation patterns
that could aid in HIV vaccine design.

A first step in overcoming this challenge is to identify consistent patterns in viral adaptation. Tools such as PhyloD (opens in new tab), PhyloD Viewer (opens in new tab), and Phylo Detective (opens in new tab) can be used to identify and visualize HIV covariation and adaptation. By identifying patterns and constraints in HIV evolution, scientists are able to focus on HIV’s weaknesses, with the goal of designing a vaccine that will be resistant to HIV mutation. The arcs in the circle pictured above, developed with the PhyloD Viewer, represent how HIV in a single patient is connected to itself as parts of it mutate.

This research delivered a statistical approach that could help further research into HIV mutation. It also led to the observation that patterns of HIV evolution are broadly predictable based on host immunogenetic profiles. In other words, we found a promising consistency in the way that HIV adapts to the human immune response, which could pave the way for vaccine design. 

It’s worth noting that this work is built on the Microsoft Biology Foundation (opens in new tab), which provides consistent file formats, statistical packages, and resources to farm out computations to clusters of machines—permitting scientists to focus on the science of modeling the virus and identifying its vulnerabilities.

—Jonathan Carlson, Researcher for Microsoft Research, eScience

The post How Microsoft Technology and Research Are Helping Create a Clearer Picture of HIV appeared first on Microsoft Research.

]]> Fighting HIV and AIDS — Journal of Experimental Medicine http://approjects.co.za/?big=en-us/research/blog/fighting-hiv-and-aids-journal-of-experimental-medicine/ Wed, 20 Jan 2010 13:03:00 +0000 https://blogs.msdn.microsoft.com/msr_er/2010/01/20/fighting-hiv-and-aids-journal-of-experimental-medicine/ Two Microsoft researchers, Jonathan Carlson and David Heckerman, working with two teams of HIV researchers at the Ragon Institute of MGH, MIT, and Harvard, and at the University of Alabama have identified new findings that could help in the fight against HIV and AIDS.  Their results appear in back-to-back articles just released in the Journal […]

The post Fighting HIV and AIDS — Journal of Experimental Medicine appeared first on Microsoft Research.

]]> Two Microsoft researchers, Jonathan Carlson and David Heckerman, working with two teams of HIV researchers at the Ragon Institute of MGH, MIT, and Harvard, and at the University of Alabama have identified new findings that could help in the fight against HIV and AIDS.  Their results appear in back-to-back articles just released in the Journal of Experimental Medicine.

http://bit.ly/8Wqh40 (opens in new tab)

The post Fighting HIV and AIDS — Journal of Experimental Medicine appeared first on Microsoft Research.

]]>