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Archive - Apr 1, 2013


Scientists Characterize Properties of Successfully Transmitted HIV-1

A new study by Los Alamos National Laboratory and University of Pennsylvania (U. Penn) scientists, together with colleagues from many other institutions, defines previously unknown properties of transmitted HIV-1, the virus that causes AIDS. The viruses that successfully pass from a chronically infected person to a new individual are both remarkably resistant to a powerful initial human immune-response mechanism, and blanketed in a greater amount of envelope protein that helps them access and enter host cells. These findings will help inform vaccine design and interpretation of vaccine trials, and provide new insights into the basic biology of viral/host dynamics of infection. During the course of each AIDS infection, the HIV-1 virus evolves within the infected person to escape the host’s natural immune response and adapt to the local environment within the infected individual. Because HIV evolves so rapidly and so extensively, each person acquires and harbors a complex, very diverse set of viruses that develops over the years of his or her infection. Yet when HIV is transmitted to a new person from his or her partner, typically only a single virus from the diverse set in the partner is transmitted to establish the new infection. The key discoveries here are the specific features that distinguish those specific viruses which successfully move to the new host, compared with the myriad forms in the viral population present in a chronically infected individual. “The viruses that make it through transmission barriers to infect a new person are particularly infectious and resilient,” said Los Alamos National Laboratory scientist Dr. Bette Korber.

Overexpressin of NUB1 Reduces Amounts of Mutant Huntingtin Protein

Researchers at Fudan University in China and the Novartis Institutes for Biomedical Research in Boston, together with colleagues from the Baylor College of Medicine, Texas Children’s Hospital, Harvard Medical School, and Massachusetts General Hospital have reported using high-throughput screening to identify genes that modify endogenous mutant huntingtin protein (mHTT) and demonstrated that the overexpression of a particular gene product (negative regulator of ubiquitin-like protein 1 or NUB1, rescues mHTT-induced death in a fruit fly model system. The authors said that NUB1 reduces mHTT amounts by enhancing polyubiquination and proteasomal degradation of mHTT protein. The process requires CUL3 and the ubiquitin-like rotein NEDD8 necessary for CUL3 activation. The authors noted that interferon- lowered mHTT and rescued neuronal toxicity through induction of NUB1. The article on this research was published online on March 24, 2013 in Nature Neurology. [Nature Neurology abstract]

Alpha Synuclein Structural Finding May Direct New Drug Development for Parkinson’s Disease

Clumps of proteins that accumulate in brain cells are a hallmark of neurological diseases such as dementia, Parkinson’s disease and Alzheimer’s disease. Over the past several years, there has been much controversy over the structure of one of those proteins, known as alpha synuclein. MIT computational scientists have now modeled the structure of that protein, most commonly associated with Parkinson’s, and found that it can take on either of two proposed structures— floppy or rigid. The findings suggest that forcing the protein to switch to the rigid structure, which does not aggregate, could offer a new way to treat Parkinson’s, says Dr. Collin Stultz, an associate professor of electrical engineering and computer science at MIT. “If alpha synuclein can really adopt this ordered structure that does not aggregate, you could imagine a drug-design strategy that stabilizes these ordered structures to prevent them from aggregating,” says Dr. Stultz, who is the senior author of a paper describing the findings that was published online on February 11, 2013 in an open-access article in the Journal of the American Chemical Society. For decades, scientists have believed that alpha synuclein, which forms clumps known as Lewy bodies in brain cells and other neurons, is inherently disordered and floppy. However, in 2011, Harvard University neurologist Dr. Dennis Selkoe and colleagues reported that after carefully extracting alpha synuclein from cells, they found it to have a very well-defined, folded structure. That surprising finding set off a scientific controversy. Some tried and failed to replicate the finding, but scientists at Brandeis University, led by Dr. Thomas Pochapsky and Dr. Gregory Petsko, also found folded (or ordered) structures in the alpha synuclein protein. Dr.

Scientists Show How Body Distinguishes Friendly Microbes from Pathogens

Researchers at the University of California (UC) Davis have shown how the innate immune system distinguishes between dangerous pathogens and friendly microbes. Like burglars entering a house, hostile bacteria give themselves away by breaking into cells. However, sensory proteins instantly detect the invasion, triggering an alarm that mobilizes the innate immune response. This new understanding of immunity could ultimately help researchers find new targets to treat inflammatory disorders. The paper was published online in Nature on March 31, 2013. The immune system has a number of difficult tasks, including differentiating between cells and microbes. However, the body, particularly the digestive tract, contains trillions of beneficial microbes, which must be distinguished from dangerous pathogens. “We are colonized by microbes. In fact, there are more bacteria in the body than cells,” said senior author Dr. Andreas Bäumler, professor and vice chair of research in the UC Davis Department of Medical Microbiogy and Immunology. “The immune system must not overreact to these beneficial microbes. On the other hand, it must react viciously when a pathogen invades.” The key to distinguishing between pathogenic and beneficial bacteria is their differing goals. Ordinary digestive bacteria are content to colonize the gut, while their more virulent cousins must break into cells to survive. Salmonella achieves this by activating enzymes that rearrange the actin in a cell’s cytoskeleton. Fortunately, cellular proteins sense the activating enzymes, leading to a rapid immune response. In the study, the researchers investigated a strain of Salmonella, in both cell lines and animal models, to determine how the innate immune system singles out the bacteria for attack.