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NEW YORK, NY, June 17, 1998 — In the long battle against AIDS, a philosophy of “know the enemy” has guided basic research. Specifically, investigators have sought a viral Achilles heel by dissecting the precise molecular choreography that unfolds as HIV penetrates the linchpin-like T cells of the immune system. Now, an unprecedented peek at that process — a viral surface glycoprotein caught in the act of binding a CD4 T cell receptor — graces the covers of both the June 18 issue of Nature and the June 19 issue of Science magazines.
The long-sought crystal structure of gp120 in action is a collaborative effort led by researchers from the Columbia University College of Physicians & Surgeons, and the Dana-Farber Cancer Institute. “The crystal structure tells us how the virus is able to bind to the receptor at the same time that it remains sufficiently changeable to avoid immune detection. There is the potential for the information to be used to design compounds that interfere and block that interaction,” says Wayne Hendrickson, Ph.D., professor of biochemistry and molecular biophysics at Columbia University and a Howard Hughes Medical Institute Investigator. Adds Peter Kwong, Ph.D., associate research scientist at Columbia and lead author on the first Nature paper, “Knowing the structure down to the atomic details will provide valuable clues for vaccine design.”
X-ray crystallography is a technique that passes X-rays through a crystal from many angles, determines their pattern of diffraction, and then assembles the data to reveal the crystal’s 3-dimensional structure, or conformation. The technique was key in solving the structure of DNA in 1953 and, more recently, in discovering the structure of HIV protease, which led to development of protease inhibitors.
But X-ray crystallography requires crystallizing a compound, which was no small feat for gp120. “The mechanisms that HIV has to protect itself from the immune system also make it difficult to crystallize,” says Dr. Kwong. Those protective parts include sequences of amino acids that vary among HIV strains and carbohydrates that cover the variable sequences. So to coax gp120 to crystallize, the researchers snipped off parts of it, using genetic clues from the virology team at Dana-Farber. “From years of work on mutagenesis and antibody binding analyses, we had a murky idea of what the protein looked like and knew the parts that could be deleted,” says Joseph Sodroski, M.D., professor of pathology at the institute.
Finally, they obtained a structure for the core of gp120 bound to both the CD4 receptor and a stabilizing antibody. This antibody, which derives from an HIV infected individual, also marks the binding site for the chemokine co-receptor. Once gp120 binds to CD4, its shape changes in a way that enables it to also bind the nearby chemokine receptor. Only then can the membranes of virus and human cell fuse and infection proceed. Having the structure of gp120 complements and extends the fuzzier snapshots of the molecule from genetic studies. “We can use mutational analysis to say ‘the CD4 binding site must be here.’ But with X-ray crystallography, we actually see it,” explains Dr. Hendrickson. And what they see in the structure is what the immune system doesn’t. “We didn’t realize before that there are whole regions (of the molecule) that the immune system never sees, forming what Joseph Sodroski calls ‘a silent face’,” he adds.
The crystal structure may revitalize efforts to create vaccines based on the immune system recognizing a portion of gp120. One such trial ended in 1996, with patients receiving a gp120-based vaccine faring no better than those who received placebo. A phase III trial of another variation on the gp120 vaccine theme received the Food and Drug Administration’s go-ahead in early June. Future trials could target other portions of the molecules that the new crystal structure reveals to be crucial to infection.
The crystal structure also reveals potential new drug targets. “At the interface of the gp120/CD4 receptor is a large cavity that is a drug designer’s dream. The deep cavity at the heart of the interaction is just begging to be filled with a high-affinity inhibitor,” says Dr. Kwong.
But the gp120 structure published now provides only one scene from a molecular dance that might, in the body, take several forms. So the researchers are fashioning other gp120s, adding back the protective sections one at a time and seeking new crystals, to provide the ammunition for a targeted, rational, multi-pronged attack against the virus. Sums up Dr. Sodroski: “This first structure will provide a foundation for people to look at this protein as the basis of a vaccine, and modify it to optimize it. It will stimulate a lot of new work.” ###