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Introducing Judith Mandl - Gaining Ground on HIV in the Course of Basic Immunological Research

bridges vol. 28, December 2010 / News from the Network: Austrian Researchers Abroad

By Juliet M. Beverly

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November 30, 2010 - The eve of World AIDS Day - "... As we approach the thirtieth year of the HIV/AIDS pandemic, we reflect on the many Americans and others around the globe lost to this devastating disease, and pledge our support to the 33 million people worldwide who live with HIV/AIDS," stated Barack Obama in the Presidential Proclamation on World AIDS Day.  "We also recommit to building on the great strides made in fighting HIV, to preventing the spread of the disease, to continuing our efforts to combat stigma and discrimination, and to finding a cure."

Finding a cure for AIDS (acquired immunodeficiency syndrome) means tackling HIV (human immunodeficiency virus), the virus that causes AIDS. Researchers worldwide have been studying HIV since it was first recognized in 1981.

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Judith N. Mandl

Just as the President made his proclamation this year, the National Institutes of Health (NIH) issued their statement on World AIDS Day 2010 entitled "Building on Success: Step by Step, Researchers Gaining Ground on HIV/AIDS." The statement marks the work of NIH researchers and milestones in the fight against HIV.  Zooming in on the NIH campus to the National Institute of Allergy and Infectious Diseases (NIAID), you will find postdoctoral fellow Judith Mandl, an Austrian scientist who is gaining ground on answering fundamental immunological questions that will aid in understanding HIV pathogenesis.

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Westward to Warwick

Judith Mandl was born and raised in Vienna, Austria. At the age of three, she was enrolled in the Vienna International School (VIS). Her education at VIS continued into secondary school, where she became interested in math, biology, and viruses. Mandl, whose father is an economist and mother a violinist, was an avid reader growing up. "At the time, my father was trying to find books that were at the biology-math synthesis with a primary focus on the population biology and evolution of viruses," said Mandl, recognizing her father as one of her early influences. "But also news reports in the 90s on the continued spread of HIV, as well as outbreaks of new emerging viruses, were an influence." During the mid-90s, while Mandl was in secondary school at VIS, there were several reported outbreaks of HIV in Eastern Europe among injected-drug users. By the time Mandl graduated from VIS in 1999, UNAIDS reported that 26.2 million people worldwide were living with HIV.

Still interested in math and biology, she sought to blend the two subjects at an academic institution with the aim of being trained in interdisciplinary research at the maths-biology interface that would apply to understanding viral epidemics.  The search eventually led her outside her homeland and westward to the computational biology program at the University of Warwick, UK. The computational biology program at Warwick was brand-new when she arrived. "I was in one of the first cohorts - there were only four people," said Mandl, recalling her small group of fellow students. "As a new program, the topics covered were developed in part according to our own interests. We were introduced to mathematical modeling of evolutionary and ecological processes, including the spread of infectious diseases between individuals."


A Transatlantic Path to the South

HIV and the CD8 & CD4 T Cells

As a chronic virus, HIV can be monitored over time to study the viral replication dynamics within a host, as well as the biology and response of T cells - a subset of white blood cells that guard the body against infection. The two types of T cells are CD4 and CD8 cells. CD8 T cells are capable of eliminating infected cells.  CD4 T cells help the body to respond to the attacking virus - they are also the host cells in which HIV replicates. CD4 T cell numbers decline during HIV infection, leading to a weakened immune system that leaves the body susceptible to other infections.

After receiving her B.Sc. with First-Class Honors from Warwick in 2002, Mandl was interested in applying mathematical modeling tools to better understand the within host dynamics of virus-immune cell interactions. "HIV infection is a particularly fascinating problem to theoreticians. It is a chronic viral infection with active virus replication in the face of ongoing immune responses," said Mandl. "In addition infection leads to the depletion of a vital T cell population, the CD4 T cells, in individuals not treated with antiretroviral therapy. Why CD4 T cells are depleted during HIV infection is an important unanswered question."

Her interest in HIV infection dynamics led her in 2006 to Emory University in Atlanta, Georgia, where Mandl joined the Population, Biology, Ecology and Evolution program. Her program included several rotations within different labs, one of which was with her dissertation advisor, Mark Feinberg, at the Emory Vaccine Center. This rotation marked the first time that Mandl would get hands-on lab experience in immunology, an opportunity that she thanks Feinberg for giving her. "Mark Feinberg was very open to me being in his lab, doing theoretical work while also getting my hands "wet" and learning to do experiments. We had a really great group of technicians who taught me lab techniques and how to structure experiments with primates."

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The sooty mangabey: a primate native to West Africa that is a natural host species for SIV. Sooty mangabeys do not progress to AIDS upon infection.
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The rhesus macaque: a non-natural host for SIV native to Central, South, and Southeast Asia develops AIDS upon infection.

At the Emory Vaccine Center, Mandl conducted experiments using the sooty mangabey, a primate native to West Africa that is a natural host species for SIV (Simian Immunodeficiency Virus). Sooty mangabeys do not progress to AIDS upon infection, while the rhesus macaque, a non-natural host for SIV native to Central, South, and Southeast Asia develops AIDS upon infection with the same virus, similarly to humans infected with HIV.  Mandl's 2008 paper, published in Nature Medicine, "Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections", investigates the immunologic mechanisms underlying the absence of AIDS in SIV-infected sooty mangabeys. The observations resulting from this research showed that there may be important differences in how immune cells that initiate an adaptive immune response to the virus "see" SIV in sooty mangabeys compared to humans. Sooty mangabeys, unlike humans infected with HIV, do not establish high levels of chronic immune activation, which is thought to be detrimental in humans infected with HIV. "If we can understand why sooty mangabeys don't get sick, maybe we can use this knowledge to develop therapies that can skew the immune response of humans so that they don't progress to AIDS," said Mandl.



Zooming In

After receiving her Ph.D. from Emory in 2008, Mandl was convinced that the next stage of her research should continue to focus more on immunological research as a means for understanding the maintenance of CD4 T cells over time during HIV infection. Supported by her NIH grant from the Office of AIDS Research, Mandl gained the opportunity to delve into fundamental immunological research using mice models. Currently in the Laboratory of Immunology, Lymphocyte Biology Section, Mandl works under Laboratory Chief Ronald Germain, investigating T-cell immunobiology.

A body's T-cell count is maintained though an equilibrium process of survival, division, and death, called homeostasis. T cells are produced in the thymus and upon their exit from this tissue, patrol the body for foreign antigens and recirculate between the blood and the secondary lymphoid organs, i.e., the lymph nodes and spleen. Once an infection is detected, naïve CD4 and CD8 T cells expand and contribute to the clearance of the infectious agent, after which they die leaving only a small number of memory T cells that are better able to respond to a subsequent infection.

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Mandl at work using two-photon excitation based intravital microscopy.

Using two-photon excitation based intravital microscopy, Mandl is able to track individual cells in vivo. This type of microscopy relies on fluorescence and a laser as a source of stimulation for the fluorescing molecules to emit light for this imaging technique. "You can look at a live mouse and see what is happening in the lymph node while it is still in the mouse, which is really cool," said Mandl who is using this "cool" tool to understand the maintenance of T cell populations. Putting these processes together has not been done and will hopefully shed light on how disruptions in lymphoid tissue, due to virus infections or chronic immune activation, can result in changes in T cell recirculation and access to homeostatic signals within secondary lymphoid organs.

"Are there things you can change to prevent the [number of] CD4 T cells from declining during HIV infection or to improve the regeneration of the CD4 T cell pool in people on therapies that suppress virus replication?" asks Mandl. "Maybe there are immunological interventions that we can develop." Basic experiments in mice will inform studies that are more difficult to undertake in humans or primates, a research possibility that Mandl says she is keeping open to return to one day. Mandl and Germain recently received another grant that will support another, related, project to explore important parameters to estimating how many memory CD8 T cells have to be generated by a vaccine in order to prevent infection with HIV. While Mandl's stay in the US is extended, she will continue to conduct fundamental immunological research that is motivated by some of the mysteries that are still unexplained in HIV.


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This article is based on an interview conducted by the author, Juliet M. Beverly, with postdoctoral fellow Judith N. Mandl at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.



References:

NIH. "Building on Success: Step by Step, Researchers Gaining Ground on HIV/AIDS" Statement from the National Institutes of Health on Worlds AIDS Day 2010. <http://www.nih.gov/news/health/nov2010/od-30.htm > (accessed November 30, 2010).

UNAIDS. "Global Report  - Fact Sheet - The global AIDS epidemic" UNAIDS
Report on the Global AIDS Epidemic 2010.
<http://www.unaids.org/documents/20101123_FS_Global_em_en.pdf > (accessed
November 28, 2010).

White House. Presidential Proclamation--World AIDS Day
<http://www.whitehouse.gov/the-press-office/2010/11/30/presidential-proclama
tion-world-aids-day
> (accessed December 2, 2010).


Mandl, J. N., A. P. Barry, T.H. Vanderford, N. Kozyr, R. Chavan, S. Klucking, F. J. Barrat, R. L. Coffman, S. I. Staprans, M. B. Feinberg."Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections". Nature Medicine 14, 1077 - 1087 (2008). Published online: September 14, 2008 | doi:10.1038/nm.1871. <http://www.nature.com/nm/journal/v14/n10/abs/nm.1871.html > (accessed November 12,2010).


Sources:

National Institutes of Health, National Institute of Allergy and Infectious Diseases. HIV/AIDS - "What Are HIV/AIDS?" NIH/NIAID. <http://www.niaid.nih.gov/topics/hivaids/understanding/Pages/Default.aspx>
(accessed November 15, 2010).

So, Peter TC. "Two-photon Fluorescence Light Microscopy". Encyclopedia of Life Sciences. Published online: May 30, 2001 | doi: 10.1038/npg.els.0002991
<http://onlinelibrary.wiley.com/doi/10.1038/npg.els.0002991/abstract> (accessed November 30, 2010).



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