Enzymes are complex protein molecules produced by cells that set in motion specific biochemical reactions. Researchers have long known that CD 4, another HIV “receptor” enzyme, plays a role in letting the virus take over healthy cells. But CD 4 can’t do the job all by itself Since the late 1980s scientists worldwide have been racing each other to discover another “coreceptor” on the surface of T-cell lymphocytes (immune-system cells that are particular targets of HIV) and other cells.
Hovanessian crossed the finish line ahead of the others–and showed for the first time just how HIV infects a healthy T cell (diagram). After the virus enters the bloodstream, a molecular protein on its surface, known as gp 120, hooks onto the CD 4 receptor on the T cell’s surface. Once attached, gp 120 exposes one of its regions, the V-3 loop, to the CD 26 receptor that’s also located on the T-cell wall. V-3, a string of amino acids whose sequence differs in varying strains of HIV, acts as the biochemical key, opening CD 26’s locked doorway. Inside that portal, the virus fuses with the T-cell membrane and enters the cell. A complete dominator, HIV destroys its host and begins reproducing.
The Pasteur researchers isolated CD 26 by concentrating on the V-3 loop section of the virus. Using computer analysis to examine 650 different V-3 sequences discovered in America, Europe and Africa, they found that although this region of the virus has an uncanny ability to alter itself radically, certain amino acid combinations remain unvarying. Mentagnier hopes that identifying CD 26’s interaction with the virus’s V-3 loop may lead to an AIDS vaccine, using antibodies to that unchanging sequence of amino acids in the V-3 loop. “The virus uses the changing parts of the V-3 loop to lead us away from the important part, just as the matador uses the cape,” he says. “So far we have been chasing the cape. But we can trick the virus by going after what it’s trying to protect, the unchanging parts of V-3.”
For more than a year, Hovanessian’s team worked to prove that CD 26–whose existence was already known–was the receptor for the V-3 loop. Using substances that inhibit the activity of CD 26, they conducted tests on mice and on human cells in the lab, measuring the level of cell penetration by the virus. “It seems clear that inhibitors specific to CD 26 block its enzymatic activity on the surface of the cells and prevent the entry of HIV,” says Hovanessian, “while antibodies prevent V-3 from interacting with CD 26.” When only CD 4 was present on the lymphocyte, the virus could not invade the cell.
The next goal is to produce the same inhibiting effect in people who are infected with HIV. But major obstacles persist. For one thing, researchers don’t know what other roles CD 26 may play in healthy cells, and they would want to block solely its enzymatic activities in T cells. For another, CD 26 may explain only how HIV behaves in the bloodstream, but not how it is transmitted through mucous membranes in sexual contact, the most common route of infection. So answers to the AIDS mystery remain elusive–but scientists understand that the best research can often provide a set of new and better questions.
