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October 20, 2010

In Research

HIV virus
An experimental compound originally designed to help Alzheimer’s patients allows HIV particles to slide past human immune cells instead of gaining a foothold for infection.

Targeting amyloid to stop HIV
Amyloid protein structures are best known for the troubles they pose in the brains of Alzheimer’s patients. Now researchers are trying to exploit their presence in semen to find a new way to stop HIV.

Scientists have created a substance that targets amyloid structures in semen and have used it to weaken the ability of HIV to infect the body’s immune cells in the laboratory. The experimental compound, originally designed to help Alzheimer’s patients by disrupting the actions of amyloid in the brain, makes it much more likely that HIV particles will simply slide past human immune cells instead of gaining a foothold for infection during sexual intercourse.

The work by Medical Center scientists, in collaboration with chemists at the University of California at San Diego, offers a new lead in the effort to develop a microbicide to prevent HIV transmission from one person to another. The findings were published online in the Journal of Biological Chemistry.

The focus of the work is an amyloid structure known as SEVI for Semen-derived Enhancer of Viral Infection, which enhances infection by sticking both to HIV particles and to the immune cells that HIV infects. It’s a middleman in the infection process—one that researchers believe is a powerful driver of HIV’s ability to infect a person during heterosexual intercourse.

“HIV viral particles are tiny and adrift amid a sea of semen and cervical mucus during sexual intercourse,” says Stephen Dewhurst, Dean’s Professor and chair of microbiology and immunology, who heads the team. “The virus must sink quickly in this fluid to have the opportunity to contact the cells that it infects. That’s what SEVI allows it to do—to literally stick around.”

Dewhurst teamed with Jerry Yang, a chemist at San Diego who previously created a compound designed to minimize the harmful interactions of amyloid with other proteins and lipids in the brain. Yang created a molecule called BTA-EG6, which fits in between the individual small proteins that cluster to form SEVI and blocks SEVI’s interactions with both the virus and the target immune cells. One key to the chemistry is the compound ethylene glycol—the central component of antifreeze—which makes it particularly difficult for SEVI to stick to the virus or to cells.

In experiments led by first author Joanna Touger Olsen, an MD/PhD student in the Dewhurst laboratory, the presence of SEVI boosted the ability of HIV to infect cells dramatically, roughly three to six times what it was without SEVI. When the nonstick compound was added, that advantage was muted, and rates of infection dropped nearly to levels when SEVI was absent. The investigators say the results must be interpreted cautiously, though, as the influence of factors such as the strain of HIV and the human cell line used in the study need to be looked at further.

The National Institutes of Health and the National Science Foundation funded the work. Read more at www.urmc.rochester.edu/news/story/index.cfm?id=2989.

soda canSugary beverages a major culprit in childhood obesity
Empty calories now make up about 40 percent of the energy consumed by children in the United States, according to new research from the Medical Center. A large percentage of those empty calories come from sugar-sweetened drinks, such as fruit juice and soda, which have little to no nutritional value.

 “These statistics are very concerning for the future health of children, especially in terms of their potential for developing heart disease early in life due to childhood obesity,” says Rae-Ellen Kavey, a professor of pediatrics and author of an editorial accompanying the article, which was published in the Journal of the American Dietetic Association. “We all develop our food preferences in childhood. Children who drink a lot of sugar-sweetened beverages, including fruit juice, are at risk to develop obesity and will find it hard to break the habit of consuming these empty calories in the future.”

The top five sources of calories for children are grain-based desserts, such as cookies; pizza; soda; yeast breads; and chicken, adding up to about 40 percent of the diet, according to the new study. Between 1989 and 1991, children consumed about 6.5 percent of their calories from sugar-sweetened drinks, according to an analysis of the Continuing Survey of Food Intakes by Individuals. The current study shows that children now consume more than 11 percent of their calories from sugary drinks. Kavey says the increase in empty calories coming from drinks is particularly concerning because liquid calories don’t satisfy hunger as well as other foods, causing children to consume even more calories.

Because of excessive weight gain associated with high consumption of sugary drinks, children who develop obesity are at higher risk of developing type 2 diabetes and consequently, early cardiovascular disease, Kavey says. Read more at www.urmc.rochester.edu/news/story/index.cfm?id=2990.

Trigger found for kidney cancer’s invasive behavior

Medical Center scientists have unlocked a strong interaction between two proteins involved in kidney cancer that help to explain the menacing invasiveness of the disease.

“We are trying to gain a better understanding of what stimulates renal carcinoma cells to be so invasive, and here we described the ability of a protein receptor, known as RACK1, to act as a scaffold and direct the communication that leads to cellular invasion,” says Guan Wu, an assistant professor of urology and corresponding author of the study.

Mutation of a tumor suppressor gene known as von Hippel-Lindau or VHL, is a key biological feature of renal cell carcinoma. VHL proteins, while binding to certain targets, are responsible for keeping in check the cycle of oxygen supply to the cells. 

When the VHL protein is absent or defective, tumor cells stimulate blood vessel growth quickly (a process called angiogenesis, required for tumor growth), which results in hyper-vascularized tumors, one characteristic of kidney cancer. Newer drugs, such as Sutent and Nexerva, have been fairly successful at choking down blood vessels and suppressing kidney cancer growth in certain patients. However, there is no magic bullet to target to kidney cancer, Wu says.

Despite a better understanding of VHL and angiogenesis, the major obstacle for scientists has been finding a link between VHL and the high degree of aggressiveness in renal carcinoma, says Xiangrong He, a research associate in the Department of Urology and a fellow at the Wilmot Cancer Center.

Generally, the process of metastasis is regulated by insulin-like growth factor-I or IGF-I. In the case of kidney cancer, the Medical Center team discovered that the RACK1 molecule plays a key role in switching on the growth factor activity in renal cancer cells that have the VHL defect.

Researchers also found they could partially disrupt or reverse cellular invasiveness in the laboratory by knocking down expression of RACK1.

“In the future, we hope to be able to genotype a patient and predict how the cancer will behave,” said He, who led the laboratory research.

Funding for the study was provided in part by the Wilmot Cancer Center. Read more at www.urmc.rochester.edu/news/story/index.cfm?id=2998.

 

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