A small minority of individuals infected with HIV — about one in 300 –Â are naturally able to suppress viral replication with their immune systems, and can keep HIV levels extremely low for years. Doctors have named these individuals “elite controllers.”
“These individuals have naturally achieved the outcome sought by HIV vaccine researchers worldwide. Â Studying them will ultimately inform the design of a more effective HIV vaccine,” saysÂ Vincent Marconi, a physician-scientist at Grady Health System’s Infectious Disease Clinic on Ponce de Leon and an associate professor in the Emory School of Medicine.
Vincent Marconi, MD
Marconi is a co-author (along with investigators at over 200 institutions) on a genomics study of elite controllers published Thursday in Science Express. Led by Bruce Walker at Massachusetts General Hospital and Paul de Bakker at the Broad Institute and Brigham and Women’s Hospital in Boston, the team of researchers scanned through the genomes of close to 1,000 elite controllers and 2,600 people with progressive HIV infection. They identified several sites linked with immune control of HIV, all in a region encoding HLA proteins.
HLA proteins play key roles in activating T cell immunity, and are also necessary for the development of T cells. They grab onto segments of proteins, called peptides, inside the cell and carry them to the cell membrane. In the right context, certain viral peptides can mark infected cells for destruction by “killer” T cells.
Previously, MGH/MIT researchers theorized that people with certain forms of their HLA genes develop T cells with a restricted repertoire, yet broader activity. Their T cells would be more likely to still recognize HIV when the virus mutates. A drawback is that these individuals may have a higher risk for developing autoimmune diseases.Â The theory is described in more detail in this Nature News article.
Marconi is continuing his part of this research into what makes elite controllers’ immune systems special, which he began at the Department of Defense Infectious Disease Clinical Research Program, in collaboration with Eric Hunter, co-director of Emory’s Center for AIDS Research, and research associate Ling Yue at Emory Vaccine Center. The research is supported by the Center for AIDS Research and the National Institute of Allergy and Infectious Diseases.
Lymphedema, or swelling because of the impaired flow of lymph fluid, can occur as a consequence of cancer or cancer treatment. Chemotherapy can damage lymph ducts, and often surgeons remove lymph nodes that may be affected by cancer metastasis. Lymphedema can result in painful swelling, impaired mobility and changes in appearance.
Young-sup Yoon, MD, PhD
Emory scientists, led by cardiologist and stem cell biologist Young-sup Yoon, have shown that they can isolate progenitor cells for the lining of lymph ducts. This finding could lead to doctors being able to regenerate and repair lymph ducts using a patientâ€™s own cells.Â The results are described in a paper published recently in the journal Circulation.
The authors used the cell surface marker podoplanin as a handle for isolating the progenitor cells from bone marrow. Previous research has demonstrated that podoplanin is essential for the development of the lymphatic system.
In the paper, the authors use several animal models to show that the progenitor cells could contribute to the formation of new lymph ducts, both by becoming part of the lymph ducts and by stimulating the growth of nearby cells.
â€œThis lymphatic vesselâ€“forming capability can be used for the treatment of lymphedema or chronic unhealed wounds,â€ Yoon says.
Isolated lymphatic endothelial cells (red) incorporate into lymph ducts (green) in a model of wound healing in mice.
The authors also show that mice with tumors show an increase in the number of this type of circulating progenitor cells. This suggests that tumors send out signals that encourage lymph duct growth â€“ a parallel to the well-known ability of tumors to drive growth of blood vessels nearby. Yoon says the presence of these cells could be a marker for tumor growth and metastasis.Â Because tumors often metastasize along lymph ducts and into lymph nodes, studying this type of cells could lead to new targets for blocking tumor metastasis.
A recent review in the journal Genes & Development summarizes additional functions of the lymphatic system in fat metabolism, obesity, inflammation, and the regulation of salt storage in hypertension.
Two presentations on Emory research at last week’s AIDS Vaccine 2010 conference concerned adjuvants. These are substances that act as amplifiers, stimulating the immune system while keeping its focus on the specific components of a vaccine.
Charlie Janeway (1943-2003)
Immunologist Charlie Janeway once described adjuvants as immunology’s “dirty little secret,” because for a long time scientists did not know how they worked. Some adjuvants can sound irritating and nasty, such as alum and oil emulsion. Alum is the only vaccine adjuvant now licensed for human clinical use in the US. Over the last few years, scientists have learned that adjuvants rev up what is now known as the “innate immune system,” so that the body knows that the vaccine is something foreign and dangerous.
Rama Rao Amara, a vaccine researcher at Emory Vaccine Center and Yerkes National Primate Research Center, and Harriet Robinson, former head of microbiology and immunology at Yerkes and now chief scientific officer at the firm GeoVax, both described extra ingredients for the DNA/MVA vaccine that Robinson designed while at Yerkes in collaboration with NIH researchers.
Imagine that HIV was a “normal” virus. An infection begins and the body responds, without getting trapped in a cycle where CD4+ T cells are consumed and the immune system is crippled.
SIV can infect sooty mangabeys but it doesn't cripple their immune systems.
The attractiveness of this idea explains some of why scientists are interested in sooty mangabeys and other non-human primates. HIV’s relative SIV can infect them, but they usually don’t develop immunodeficiency.
At last week’s AIDS Vaccine 2010 conference, Cynthia Derdeyn reported her laboratory’s recent results investigating sooty mangabeys, which don’t develop high levels of neutralizing antibodies against SIV when infected. Derdeyn’s group at Emory Vaccine Center andÂ Yerkes National Primate Research Center studies how HIV and SIV evade the immune system.
Paula Frew, PhD
The scientific part of the AIDS Vaccine 2010 meeting began Tuesday evening with an exciting summary of issues facing the field from NIAID director Tony Fauci. But before that, participants in this yearâ€™s conference got a chance to warm up with several â€œsatellite sessions.â€
One of them, â€œEffective Community Engagement in HIV Vaccine Research Among Communities and Researchers,â€ was organized by Paula Frew, PhD, director of health communications and applied community research at Emoryâ€™s Hope Clinic.
Two prominent themes emerged from this session. The first was that community members should be involved in clinical trials at every step of the process: from design and recruitment to dissemination of results.
â€œIn the past, scientists often came to the community late in the process, after a protocol for a study was already approved, and said: â€œWill you support what weâ€™ve already decided?â€ said Steve Wakefield of HIV Vaccine Trials Network. â€œThis doesnâ€™t work.â€
The Joint United Nations Programme on HIV/AIDS and AVAC presented proposed guidelines for â€œgood participatory practice,â€ analogous to good clinical practices.
Another theme that emerged from the satellite session was the search for more flexible â€œadaptiveâ€ clinical trial formats. Glenda Gray from South Africaâ€™s University of the Witwatersrand emphasized that adaptive trials could be faster and avoid enrollment of large numbers of patients unnecessarily.
This week a variety of media outlets and science-oriented Web sites had fun with research at Emory — published recently in PNAS — investigating a gene that appears to limit some forms of learning and memory.
Mice with a disabled RGS14 gene remembered objects in their cages more easily and learned to navigate water mazes better, pharmacologist John Hepler and his colleagues found.Â Since the presence of a functional RGS14 gene holds mice back mentally, Hepler and his colleagues have been jokingly calling it “the Homer Simpson gene.”
This description struck a chord; the Atlantic magazine even embellished the story with a video showing the “D’oh”-ey cartoon character evolving from a single cell into a human couch potato.
It’s important to recognize that smart mice are not so surprising to scientists anymore. Back in 1999, scientists at Princeton announced the creation of “Doogie Howser” mice (named after a precocious doctor from another TV series). These critters performed better than normal lab mice in some of the same tests that Hepler’s team used to evaluate the RGS14-deleted mice.
One important difference: the Doogie mice had all their normal genes, and were overproducing a NMDA receptor gene involved in helping neurons communicate. Still, as a helpful 2009 round-up in Nature Reviews Neuroscience explains, scientists have found several single-gene knock-out mice that do better on tests of learning and memory. Many of these genetic alterations affect the process of long term potentiation, a process where neurons that get stimulated at the same time have the connections between them grow stronger.
RGS14 is turned on primarily in the CA2 region of the hippocampus
What makes the RGS14 gene an intriguing case is that it’s primarily turned on in the enigmatic CA2 region of the hippocampus. The CA2 region is normally relatively resistant to long-term potentiation and is also more hardy in situations of stroke or seizure.
Hepler observes that the vasopressin receptor 1b gene is also turned on predominantly in the CA2 region, and seems to be involved in aggression and social memory. He and his colleagues are planning to examine whether the RGS14-disabled mice have altered capabilities in those areas. Conveniently, Larry Young’s laboratory at Yerkes National Primate Research Center has been investigating the functions of vasopressin receptors in voles.
One last note: scientists in Spain have reported in Science that they can generate a variety of smart mice by putting the RGS14 gene on overdrive in a part of the brain where it’s not usually turned on. So whatever precise function RGS14 has, it doesn’t always dumb things down.
In the September issue of the Journal of the American Academy of Dermatology, Jack Arbiser and colleagues describe the use of gentian violet to provide some relief to a patient who came to the emergency room with a painful skin irritation. Arbiser is a professor of dermatology at Emory University School of Medicine.
A coal-tar dye which is inexpensive and availableÂ over the counter, gentian violet was first synthesized in the 19th century. It has been used as a component of paper ink, a histological stain, and an antibiotic or antifungal agent, especially before the arrival of penicillin.
“Clinicians should not forget about gentian violet for immediate pain relief and antibiotic coverage,” the authors conclude in their case report.
Biopsy of the patient's irritated skin shows that the gene angiopoetin-2 (dark brown) is turned on
In addition to its antibiotic properties, Arbiser reports that gentian violet has antiinflammatory effects, possibly because of its inhibition of the enzyme NADPH oxidase and the gene angiopoetin-2.
Posted on September 9, 2010
Thomas Kukar, a new Emory faculty member in pharmacology, is participating in a charity bicycle ride for Alzheimer’s disease research called the Alzheimer’s Breakthrough Ride. On Thursday and Friday, he will be riding from Oklahoma City, OK to Wichita, KS.Â Tomorrow’s ride is 100 miles, and it’s supposed to be 97Â°F in Wichita.
Thomas Kukar, PhD
Kukar’s willingness to take on this challenge indicates that he shouldn’t have too much trouble adjusting to Atlanta’s climate. He comes to Emory from the Mayo Clinic in Jacksonville. There, he investigated potential drugs that could change how the body produces and processes beta-amyloid, a toxic protein fragment that builds up in the brains of people with Alzheimer’s.
The money raised by the bicycle ride goes to the Alzheimer’s Association.
Posted on August 18, 2010