HIV Research Solves Structure

Harvard Medical School (HMS) researchers say they have achieved a significant victory in the ongoing campaign against HIV by uncovering how the virus changes shape, which has been the main obstacle to developing an effective vaccine.

The discovery by Professor of Biological Chemistry and Molecular Pharmacology Stephen C. Harrison and his post-doctoral fellow, Instructor in Pediatrics Bing Chen, is featured in an article in the Feb. 24 issue of Nature.

The two scientists and their team crystallized a key protein, known as gp120, found on the membrane of HIV—the virus that causes AIDS. By taking an X-ray image of the crystallized structure, they were able to reveal its shape.

When gp120 binds to CD4 receptors, which are found on the surface of HIV’s target cells, it initiates a cascade of events that alters the shape of the complex, allowing HIV to evade the antibodies of the immune system.

Although the structure of the bound form was discovered seven years ago, the unbound form—that is, gp120 before it attaches to a target cell—remained too unstable to yield crystals that would provide a clear image of its shape.

The key to Harrison’s breakthrough is the similarity between HIV and SIV, or simian immunodeficiency virus, and “noticing that this particular construct derived from SIV is stable” enough to yield crystals, whereas “standard HIV constructs are not stable,” said Harrison.

“When two proteins are as similar in their amino acid sequences as these, you can be confident that they have similar structures and structural changes,” he added.

Scientists have long searched for a way to induce the formation of antibodies that can recognize different strains of a single virus, like the rapidly mutating HIV.

This discovery provides insight into another route of HIV inhibition. If the shape transformation is blocked, HIV cannot fuse with the target cell membrane. This fusion is the mechanism that allows entry into the cell.

Recanati Professor of Medicine Jerome E. Groopman, who is also a leader in HIV inhibition, said Harrison has “figured out the gymnastics of several viruses, which is enormously valuable in designing molecules that interfere with the process.”

Groopman added that although there are “always uncertainties in translating laboratory discoveries into safe, effective clinical treatments, his strategy is the most rational.”

Another observation relevant to the newly revealed structure is that “we see a potential binding site for a small molecule,” Harrison said. There is a “deep pocket on the surface, and that pocket needs to change its shape for CD4 to bind.”

If a small molecule could be induced to bind to that pocket, it would inhibit the shape transformation the virus would need to undergo in order to infect target cells.