Scientists get clear picture of HIV conspirator

Chinese and U.S. researchers have gotten the first close look at one of the two HIV " conspirators" that help the AIDS-causing virus invade human immune system. The researchers reported in the Friday issue of the journal Science that they decoded the high-resolution structure of a human protein called CCR5 and called it a "breakthrough" toward the next generation of anti-HIV drugs. Although the HIV virus was initially discovered to infect cells via a receptor called CD4, researchers found in 1996 that HIV infection requires a co-receptor, usually CCR5. By binding to it, an HIV protein can fuse to the cell membrane beneath, ultimately digging its way inside the cell. A minority of HIV strains also use the alternate co-receptor CXCR4 instead of CCR5. Scientists therefore have sought to develop anti-HIV drugs that block the virus from binding to CCR5 or otherwise render the receptor inactive. Yet only a handful of CCR5-inhibiting compounds have been developed so far, and no one knows exactly how they work. "One thing that we've lacked is a high-resolution molecular ' picture' of the CCR5 receptor structure that we can use for precise drug design," Beili Wu, professor at the Chinese Academy of Shanghai Institute of Materia Medica, part of the Chinese Academy of Sciences, said in a statement. In their study, Wu and colleagues used an anti-HIV drug called Maraviroc to bind an engineered CCR5 receptor and then purified and crystallized the resulting complex at a very high resolution. "Maraviroc was thought to lock CCR5 into an inactive conformation, and so we wanted to 'see' that conformation at high resolution," Wu explained. The resulting crystallography data revealed a fine-grained picture of CCR5's HIV-resistant conformation and the drug's precise binding site on CCR5, the researchers said. The structure of CXCR4, the other receptor that HIV uses to get into cells, was solved by some of these same authors and published in Science in 2010. "The human CXCR4 and CCR5 structures are key breakthroughs for the field, and a long sought after goal," said study co-author Raymond Stevens, a professor at the U.S. Scripps Research Institute. "Perhaps most exciting is that with CXCR4 and CCR5 protein material available, the door is now open to using multiple biophysical studies and knowledge, to better understand how HIV infectivity occurs." "With both the HIV co-receptor three-dimensional structures, it is likely we will see the next generation of HIV therapeutics," Stevens added.