Using sophisticated microtechnology, scientists have made the first precise three-dimensional map of a tiny strand of protein that the AIDS virus uses as its entry point to attack the body's immune system.
Unless it can fasten to this critical target receptor, the virus is harmless. Experimenters have tried for years to use drugs that mimic the structure of the receptor protein and act as "decoys" to attract the virus. But those efforts have met with limited success, in large part because the exact atomic structure of the binding site was not known. Now it is, and many medical experts are hopeful that the new research will hasten development of new treatments for AIDS.
The findings, reported by two independent research teams in today's issue of Nature, have "enormous implications for the development of directed specific therapy," said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.
The human immunodeficiency virus (HIV) that causes AIDS does its damage by latching on to a particular kind of cells, called T lymphocytes, which normally roam through the blood and attack infectious agents. After attaching itself to the T cell, HIV penetrates the membrane and commandeers the T cell's genetic apparatus, forcing it to make new copies of the virus instead of new T cells. As a result, the virus proliferates while the number of healthy T cells decreases, weakening the immune system and leaving the victim vulnerable to a host of infections.
None of this can happen, however, unless the virus can literally get a handle on one specific receptor on the T cell membrane: a protruding flap of protein, called CD4, into which a corresponding piece of HIV fits in lock-and-key fashion. Thus, scientists have long reasoned, flooding the bloodstream with synthetic CD4 receptors would trick HIV into binding to them instead of the natural CD4, leaving the immune system intact.
Until now, however, no one has been sure exactly what the protein looked like.
That knowledge is important, Fauci said, because "if you didn't know precisely what the 3-D structure of the molecule was, and you made a drug to block the binding of the virus to the cell, you might inadvertently interfere with the normal functions of this particular multifaceted molecule. This way you can interfere with the one function you want to alter."
In the last five years researchers developed a form of CD4 that could be injected into AIDS patients. So far, the results have been disappointing. But the new map "certainly will improve" scientists' ability to refine the forms of CD4 currently being tested, Fauci said.
"The reason CD4 as such doesn't seem to work well is that it doesn't bind as tightly as expected to the virus," said Stephen Harrison, a biochemist at Harvard University and the Howard Hughes Medical Institute in Cambridge, Mass., and leader of one of the research groups. "And therefore you can't get enough of it into the bloodstream to inhibit the virus from infecting other cells." But since HIV actually binds to only about 5 percent of the whole CD4 molecule, the new structural information could lead to more easily fabricated drugs involving "a much smaller entity that wouldn't even need to be a protein."
The principal method used in the 3-D mapping was X-ray crystallography, a technique used to ascertain the shape of atomic structures too small to be seen using visible light. The chemical to be examined is converted to solid crystal form, placed in a minuscule glass container and bombarded with X-rays from various directions. When the rays strike the faces of the crystal lattice, they are scattered in directions determined by the angle and atomic makeup of the parts of the crystal they hit. Sensors record the scatter pattern, which is fed into a computer that calculates the alignment of the crystal planes and the location of different kinds of atoms on the lattice.
"These are phenomenally elegant scientific studies," said Samuel Broder, director of the National Cancer Institute, one of the first groups to test injectable forms of CD4. He said such "basic research almost always has a practical application, but the specific form it takes is not obvious."
The potential, however, is large. "Because CD4 really belongs to a large family of special molecules that evolved to serve in recognizing biological determinants" such as the presence of foreign bodies, Broder said, the CD4 map might make it possible "to develop powerful new ways of amplifying or interfering with immune reactions in general," including autoimmune diseases.
In the near term, however, the new research is unlikely to have an immediate effect on AIDS treatments. "There is no precedent for going from the structure of the receptor to the design of a drug," said Harrison. "It's uncharted territory, and one has to be highly cautious about whether this is a step forward in AIDS therapy."
The CD4 research, which also was carried out at Columbia University, was funded by the Howard Hughes Medical Institute and the National Institutes of Health.