For a decade, AIDS researchers have known one thing about how the virus infects human immune cells: it binds to a receptor molecule called cd4 on the cell surface. But they’ve also known that cd4 is not enough. Even if an animal has been engineered to produce human cd4 on its immune cells, those cells cannot be infected with hiv. Last May, biochemist Ed Berger of the National Institutes of Health and his colleagues announced that they had finally succeeded--where many before them had failed--in identifying an elusive coreceptor that makes certain human cells peculiarly vulnerable to hiv. Their finding unleashed a storm of papers that not only help clarify our understanding of aids but also may lead to new treatments for the disease.
Berger’s method was straightforward: he and his colleagues added hundreds of different genetic sequences, one by one, to nonhuman cells that had been engineered to express human cd4, until they finally found one genetic sequence that made the cells susceptible to hiv. That sequence encoded the coreceptor, which Berger has dubbed fusin--and which is found along with cd4 on the surface of human T cells. One theory is that binding to cd4 brings the virus into the right position to interact with a nearby molecule of fusin. That interaction may change the shape of hiv’s protein coat so that the virus can fuse with the cell membrane and funnel its genes into the cell.
Of course, that role cannot be fusin’s original purpose in life-- quite the opposite. Fusin, Berger’s group found, belongs to a large family of cell-surface receptors whose purpose is to glom on to chemokines: molecular sos signals with which immune cells rally themselves to the site of an infection. Within weeks of Berger’s report, a spate of papers had appeared identifying at least four other chemokine receptors through which hiv can gain entry into a cd4-bearing cell. Why those receptors in particular? No one knows for sure. But chemokine receptors happen to be made of proteins that dive in and out of the cell membrane several times-- which may make them ideal docking sites for a virus that must wallow in a cell’s membrane in order to infect it.
In any case, the discovery that chemokine receptors are also hiv coreceptors helps us make sense of some earlier, puzzling findings. The gist of those findings was that some chemokines seem to inhibit the spread of virus in T cells. As a result of Berger’s discovery, researchers now suspect that chemokines somehow shut the door on hiv, perhaps by occupying the coreceptor or by somehow reducing its availability in some other way.
Among the first cells that hiv typically invades are macrophages, the scavenger cells that patrol body tissues looking for infection. Macrophages don’t carry fusin. On them the virus exploits a different chemokine receptor, called ckr-5, which was identified this past year by Dan Littman of the Howard Hughes Medical Institute at New York University and his colleagues. Littman speculates that the virus must first infect macrophages, even though T cells are its ultimate host, because only infected macrophages can activate T cells, turning on their internal protein factories--which hiv needs to churn out more hiv. Whether or not that is true, the virus seems to have the ability to switch its focus from one coreceptor to another, from ckr-5 to fusin, as the infection progresses.
That might make hiv sound more invincibly cunning than ever. But it also suggests a new weakness that researchers may be able to exploit. Three other studies published in 1996 found that people with defective ckr- 5 receptors are resistant to HIV infection. Moreover, the defect doesn’t seem to harm their health in other ways. With the right small-molecule drug that would bind to one of its nooks or crannies, it might be possible to disable the receptor--and thus erect a barrier to the progress of hiv infection.
And with the recognition of the importance of chemokine receptors, aids researchers may have broken through a barrier of their own. I’ve never seen anything like this, says Berger, whose paper last May started it all. We opened up the floodgates.
