In a breakthrough six years in the making, an international team of researchers has determined the precise atomic structure of a cell-surface receptor that’s used by most strains of HIV to infect human immune cells. The finding could result in medicines that block the process.
HIV researchers have been making great strides recently — and thank goodness for that. Since making its unwelcome debut in the early 1980s, HIV/AIDS has killed more than 28 million people worldwide, with more than 34 million people currently living with the virus infection.
Back in March, scientists functionally cured a baby infected with HIV. A week later, doctors announced that a similar technique had effectively cured 14 adults. And late last year Canadian researchers announced that their efforts to create the world’s first HIV vaccine had cleared a major hurdle after a successful Phase I trial. Relatedly, it was only yesterday that researchers from Oregon Health & Science University announced that they have developedan HIV/AIDS vaccine that can completely clear an AIDS-causing virus from the body. There’s even a drug, called Truvada, that’s proven to reduce the risk of HIV infection.
Visualization = Understanding
The target is a receptor called CCR5 — and it’s one of two main entry points that HIV uses to launch its attack on the human immune system; CCR5 is a protein on the surface of white blood cells that’s involved in the immune system, acting as a receptor for chemokines (signalling proteins secreted by cells). After binding to it, an HIV protein fuses to the cell membrane beneath as it digs its way inside the cell. Infection ensues.
The other receptor that performs this feat is CXCR4. Together, the two belong to a family of receptor proteins called G-protein-coupled receptors (GPCRs) which regulate a host of functions in the human body. These receptors are crucial to scientists when designing drugs.
Until now, however, scientists haven’t been able to properly visualize the precise molecular structure of these labyrinthine receptors. Previous studies have successfully solved CXCR4’s structure, but the exact way it recognizes and binds to HIV viral proteins has remained a mystery.
Indeed, without a hi-res molecular “picture” of the receptors, designing drugs is difficult — if not impossible.
Maraviroc to the Rescue
To capture the high resolution, three-dimensional atomic structure of the receptors, a team supported by both US and Chinese research agencies (including The Scripps Research Institute in California) considered Maraviroc, an antiretroviral drug and entry inhibitor used to treat HIV-1. It’s a receptor antagonist that binds the co-receptor, making it unavailable to circulating HIV.
In this artistic impression, the HIV drug Maraviroc grabs hold of CCRF in an inactive configuration, preventing HIV from using the receptor to enter cells. (Courtesy of the Wu lab)
In the new study, the researchers demonstrated the precise spot where Maraviroc attaches to cells and blocks HIV’s entry.
Maraviroc was used by the researchers to bind an engineered CCR5 receptor. It was then purified and crystallized, resulting in a receptor/drug complex that measured 2.7 Angstroms. By looking at this bound complex at such a high resolution — where the receptor was made inactive and unresponsive to HIV — the scientists were able to catch a glimpse of the molecular pathway by which HIV fuses with cells, including the molecular-scale quirks that allow some strains of HIV to escape CCR5 inhibitors.
Image: CCR5 side-by side with alternate HIV co-receptor CXCR4. (Courtesy of the Wu lab)
The study, which appears in Science, will help scientists to both improve existing HIV drugs based on CCR5 inhibition and to design new drugs altogether.
“We hope that the structure we determined can be used to understand the molecular details of the current viral strains of HIV entry, to develop new molecules that can inhibit both CXCR4 and CCR5 receptors, and to block future strains that might emerge and be addressed with second generation HIV entry inhibitors,” noted Beili Wu, a researcher from the Chinese Academy of Sciences’ Shanghai Institute.
via i09 Read the entire study at Science Express .
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