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RESEARCH BRIEFS
Monkey Protein Blocks Infection by HIVHIV-1 must run a gauntlet of unfriendly immune cells before it enters a host cell. It now appears that some cells have their own way of making the intruder feel unwelcome--namely, by interfering with the virus's ability to remove its coat.HIV-1 consists of a core of RNA and enzymes surrounded by a protective layer of capsid proteins. To release its contents--and to replicate--the virus must remove this capsid coating, but it must do so in a specific fashion. Matthew Stremlau, Joseph Sodroski, and their colleagues found that Old World monkeys harbor a protein, TRIM5-alpha, that interferes with the HIV-1 uncoating process.
Old World monkeys, those from Africa or Asia, have long been known to resist infection by HIV-1. To find out the secret of their immunity, the researchers inserted snippets of rhesus monkey DNA into human cells in an attempt to see which pieces of genetic material would confer HIV-1 resistance. They generated two resistant clones, both carrying a piece of cDNA coding for TRIM5-alpha. TRIM5-alpha was expressed in human cells that were then exposed to HIV-1. The cells exhibited a marked inhibition of infection. Though it is not clear how exactly the TRIM5-alpha works, it appears to bind the capsids and ubiquitinate them, thereby tagging them for destruction. The human TRIM5-alpha does not effectively bind the HIV-1 capsid coat, but some human variants may be more capable than others--which could help to explain why some HIV-infected people do not develop disease for decades. In the future, therapies might be designed to increase the effectiveness of human TRIM5-alpha or to administer the more potent monkey version. --Misia Landau
Iron Maidens May Be at Higher Risk for DiabetesObesity remains the queen of risk factors for developing type 2 diabetes, but in healthy women, a high iron level in the body appears to be at least as risky as a lack of exercise or a diet rich in hydrogenated oils or refined carbohydrates, says an HSPH study in the Feb. 11 Journal of the American Medical Association.The researchers, led by Rui Jiang, a research fellow in the Department of Nutrition at HSPH, went back to the blood samples of 698 women in the Nurses' Health Study who developed diabetes during 10 years of follow-up. He compared them to women of similar age and race who did not develop the disease. Women who topped the charts in ferritin, a protein that stores thousands of iron atoms in the blood and tissue, were nearly three times more likely to develop diabetes than those with the lowest concentrations. Another biomarker showed a 2.5 times higher relative risk for women with the highest iron storage in blood and tissue compared to women with the lowest, the researchers report. "The iron levels in the high-risk group are not considered abnormal, but the increased risk is pretty remarkable," said Frank Hu, senior author of the study and HSPH associate professor of nutrition and epidemiology. Similar studies show that a sedentary lifestyle or eating more trans-fatty acids, more refined carbohydrates, or less fiber all independently predict the risk of diabetes. The results help make a more definitive case for the relationship between iron and diabetes, Hu said. Five years ago, a smaller study in Finland reported similar findings in healthy men. Type 2 diabetes is a common clinical problem in diseases of extremely high iron accumulation, such as hemochromatosis, caused by a genetic defect in regulation of iron absorption that affects up to 1 in 250 people of northern European ancestry. "In the past, we have focused on insulin or glucose metabolism in the pathophysiology of type 2 diabetes," Hu said. "This is a different pathway. Iron is a double-edged sword. On one hand, our body needs iron for carrying oxygen and other cell functions; on the other hand, too much iron increases oxidative stress, causing tissue damage. Our results could open a new door for research." --Carol Cruzan Morton
Protein Interferes with RNAiLike smart bombs, small interfering RNAs (siRNAs) are designed to recognize and destroy the messenger RNA products of one gene among thousands in a living organism. This ability of siRNAs to act like guided missiles lets researchers study the function of single genes by knocking down their protein expression. The selectivity of RNAi also offers a promising new therapeutic approach against viruses, including HIV, and cancer.But RNA interference does not always work. Research from the lab of Gary Ruvkun, HMS professor of genetics at Massachusetts General Hospital, reveals at least one reason why. In C. elegans, RNA interference can itself be interfered with by an enzyme that he and his colleagues call ERI-1. Research by postdoctoral fellow Scott Kennedy and graduate student Duo Wang, published in the Feb. 12 Nature, shows that ERI-1 works by destroying the siRNA warheads before they can reach their mRNA targets. In the nematode C. elegans, where RNA interference was first discovered, neuronally expressed genes, in particular, resist knockdown by siRNAs. Kennedy started with worms that expressed a green fluorescent protein in neurons and did not show a drop-off of green protein in response to RNAi. He then looked at about 50,000 worm mutants for the rare animal in which RNAi did block expression of the labeled neuronal protein. The strongest inhibition he saw occurred in worms with mutations in a gene that he dubbed eri-1 (short for enhanced RNAi). Kennedy demonstrated that the ERI-1 protein from worms or the related protein from humans is a nuclease that can degrade siRNAs, but not other kinds of double-stranded RNA. ERI-1 turns out to be most abundant in neurons, which may explain why neuronal genes are the least amenable to RNAi knockdown in C. elegans. But eri-1 mutants gave better responses to RNAi in non-neuronal cells as well, suggesting that in most cell types, getting rid of ERI-1 is sufficient to stabilize siRNAs and let them do their work more effectively. "The truth is that RNAi doesn't always work so well," said Kennedy. "We thought that if we could identify factors that normally inhibit RNAi in C. elegans and then identify the equivalent factors in humans, one might be able to use this information to increase the effectiveness of RNAi in humans." In a test tube at least, the human ERI-1 enzyme equals its worm counterpart in destroying siRNAs, raising the possibility that inhibitors of human ERI-1 could be used to boost medicinal RNAi therapies. --Pat McCaffrey |
