Scientists hopeful they’re closer to HIV vaccine after new imaging insights
Using powerful microscopes, scientists have observed the weaponry of HIV in action and gained key insights that may finally allow researchers to create a vaccine capable of fighting the virus that causes AIDS.
The sophisticated imaging technology employs lasers and fluorescent dyes to examine molecules 10,000 times smaller than the width of a human hair. The resulting view of the infamous protein spikes that stud the surface of HIV sheds new light on how the virus both evades and attacks key immune cells.
Scientists even videotaped the structures as they changed shape in what researchers described as a rapid, unending “dance.” They also observed how a class of rare, super-potent antibodies collected from AIDS patients can halt this dance by locking the structures into a harmless position. Once frozen in place, the spikes were unable to initiate entry into host cells.
The findings, which were published Wednesday in the journals Nature and Science, provide crucial insights into the behavior of HIV, experts said.
“Personally, working in the HIV vaccine field for 16 years, I have never been so positive,” said Rogier Sanders, a Cornell University microbiologist who studies the spikes but was not involved in the new research. “I think the coming year will see some major steps forward thanks to this.”
HIV’s preferred targets are CD4 T-cells, the white blood cells that help direct the body’s immune response in times of crisis. When the virus bumps into one of these cells, the spikes latch onto the cell’s surface and pull the virus so close that it merges with the cell and dumps its genetic material into the host. Then the doomed cell begins mass-producing copies of the virus, which go on to invade more immune cells.
Ideally, the body fends off attacking viruses by producing antibodies — tiny Y-shaped proteins that fasten to the surface of foreign microbes and prevent them from entering cells or flag them for destruction. In the case of HIV, however, the spikes are expertly camouflaged in a coating of sugar that fools the immune system into thinking the virus is part of the human body.
It’s this camouflage that has made it so difficult for scientists to develop an HIV vaccine.
To examine the spikes more closely, researchers turned to the field of single molecule microscopy — an observation technique that was recognized with the Nobel Prize in chemistry on Wednesday. The technology allows scientists to peer into the inner workings of cells or viruses that cannot be seen with conventional microscopes.
The researchers observed that the HIV spike was not only covered by sugars, but it cycled between three specific shapes, each of which affected the virus’ ability to infiltrate cells. These configurations could last for seconds, or just milliseconds, before changing into another shape.
“This was a bit surprising,” said Jason Gorman, a coauthor of both studies and a vaccine researcher at the National Institute of Allergy and Infectious Diseases. “Nobody had ever seen how the spike moves in real time before.”
The spike’s shape-shifting included an open and a closed position, as well as another configuration that researchers have yet to fully describe.
Walther Mothes, a professor of microbial pathogenesis at Yale School of Medicine and a coauthor of both papers, said this shape-shifting suggested a critical vulnerability of the virus.
For HIV to latch onto and fuse with a host cell, the spike must assume its open configuration. When it does this, it must remove some of its camouflage and reveal its true nature to circulating antibodies. Because of this, the virus keeps the spike closed most of the time, and opens only very briefly.
“This is a big step forward in our understanding of the structure and dynamics of the spike,” Mothes said.
The researchers reasoned that if the spike was frozen in the closed position, the virus could be neutralized. A series of experiments with antibodies taken from AIDS patients appeared to confirm this hypothesis.
In the last few years, scientists have realized that some AIDS patients have developed broadly neutralizing antibodies that are able to see through HIV’s disguise. Mothes and his colleagues showed that these antibodies were able to attach to the HIV spike and keep it in the closed position.
“They actually function as inhibitors and don’t allow it to open up,” Mothes said. “They lock it down.”
A successful vaccine would trigger the production of similar antibodies before infection occurs, scientists believe.
In a commentary published in Nature, Sanders and John Moore, a Cornell professor of microbiology and immunology, wrote that numerous obstacles remained in developing a vaccine, but that the new structural data would undoubtedly help.
In fact, they wrote that this new research constitutes “a frank warning to the virus.”
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