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FRET Offers Real-Time Look at HIV Infection Process

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Scientists can now study the motion of HIV proteins on the surface of the virus, opening new possibilities for fighting the disease.

A team at Weill Cornell Medical College used single-molecule fluorescence resonance energy transfer (smFRET) imaging to get real-time view of how the proteins attack and infect human immune cells.

“Making the movements of HIV visible so that we can follow, in real time, how surface proteins on the virus behave will hopefully tell us what we need to know to prevent fusion with human cells,” said Dr. Scott Blanchard, an associate professor of physiology and biophysics and associate director of the chemical biology program at Weill Cornell. “If you can prevent viral entry of HIV into immune cells, you have won.”

This structure shows the two proteins (in red and gold) and sugars (in green) that mediate HIV’s fusion with host cells. Courtesy of Nature/Pancera et al.

The researchers’ work ties together two studies.

One of the studies, published in Science, details how the new technology can look at the processes happening on the surface of the HIV particles. Such data could be used “to screen the impact of drugs and antibodies that can shut it down,” Blanchard said.  

The other related study, published in Nature, describes how x-ray crystallography can be used to image the 3-D structure of an HIV protein.

In the Science study, the researchers developed fluorophores and inserted them into the virus’ outer covering (the HIV-1 envelope). With two of the beacons in place, smFRET imaging was used to visualize how the molecules moved over time as the virus proteins changed position.

The HIV-1 envelope mediates viral entry into host cells, the researchers wrote in the study, noting that this is key to the virus’ ability to infect human immune cells — specifically those that carry CD4 receptor proteins.

The envelope consists of three trimers — gp120 and gp41 proteins positioned close together that open up like a flower in the presence of CD4 — exposing the gp41 subunit that is essential for infection.

“There are 10-20 such envelope trimers on the surface of each HIV particle and they mutate rapidly, thereby evading typical immune responses,” Blanchard said. “Many scientists believe that the particles remain in one conformation until they come across a CD4-positive cell. But we saw that the proteins dance when no CD4 was present — they change shape all the time.”

The researchers observed how the viruses responded when synthetic CD4 was introduced. Antibodies known to exhibit some effectiveness acted to prevent gp120 from opening, correlating with a decrease in the virus’ ability to infect cells.

The related Nature study, led by a team from the National Institute of Allergy and Infectious Diseases (NIAID) in conjunction with Weill Cornell researchers, used x-ray crystallography to capture a 3-D structure of one of the conformations discovered in the Science study.

“The antibodies used in the crystallography study are ones that we observed to stop the dance of the HIV envelope proteins, pushing the trimer assembly into a quiescent, ground state,” Blanchard said.

Both imaging techniques could help scientists describe the functions of molecules from the perspective of motion.

The work featured in the Science study was funded by the National Institutes of Health, the Irvington Fellows Program of the Cancer Research Institute, the China Scholarship Council-Yale World Scholars, the International AIDS Vaccine Initiative's (IAVI) Neutralizing Antibody Consortium, the NIH Intramural Research Program, the Bill & Melinda Gates Foundation and the U.S. Agency for International Development (USAID).

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Jan 2015
The emission of light or other electromagnetic radiation of longer wavelengths by a substance as a result of the absorption of some other radiation of shorter wavelengths, provided the emission continues only as long as the stimulus producing it is maintained. In other words, fluorescence is the luminescence that persists for less than about 10-8 s after excitation.
Research & TechnologyimagingBiophotonicsAmericasHIVAIDSWeill Cornell Medical Collegefluorescencesingle-molecule fluorescence resonance energy transfersmFRETFRETScott BlanchardBioScan

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