The guessing may finally be over. Writing in the journal Science last week, researchers at the National Institute of Al- lergy and Infectious Diseases (NIAID) identified a previously unknown coreceptor, a cell-surface appendage that they’ve dubbed ““fusin.’’ Their findings suggest that although HIV can’t invade cells by means of the CD4 receptor alone, it readily infects those displaying both CD4 and fusin. ““We would have been happy just to know what the cofactor was,’’ says virologist Edward Berger, who led the team. ““But we got more than we bargained for.’’ Indeed, the molecule they discovered could both transform our understanding of how HIV causes disease and point the way to new treatments.
Unmasking the new receptor required several molecular hat tricks. First, the researchers created mock HIV by outfitting a line of cells with ““envelope’’ protein, the tiny molecular appendage the virus uses to latch onto its target (chart). Next, they created CD4-bearing mouse cells that would react to a blue stain whenever the mock HIV managed to fuse with them. Finally, the researchers collected genes for the 100,000 other proteins that human CD4 cells can display. The object was to find out which of those proteins would open the door to infection.
Not surprisingly, cells containing all 100,000 genes were more susceptible than those equipped only with CD4. So Berger’s team divided the library of genes into sections they could test individually. By outfitting cells with one group of genes after another, and eliminating the groups that didn’t promote infection, the researchers gradually narrowed the pool of suspects. Eventually, fusin emerged as the culprit.
Why is that worth knowing? For one thing, it may help explain why some of us are less susceptible to HIV infection than others, and why some infected people stay healthy for such long periods. Late last year, researchers discovered that people with natural resistance to HIV produce molecules known as chemo- kines, which keep the virus from infecting otherwise vulnerable cells in a test tube (NEWSWEEK, Dec. 18). Fusin appears to be a chemokine receptor. If so, then logic suggests that chemokines may thwart HIV’s spread by binding with fusin receptors, leaving them inaccessible to the virus.
Whether that’s true or not, blocking the fusin reaction now seems a likely approach to treatment. If a drug could do that, it might slow the spread of the virus within the body, turning countless infected people into ““long-term nonprogressors.’’ Meanwhile, the discovery of fusin should ease the task of studying HIV infection in small animals such as rabbits. A rabbit normally resists HIV infection. But if scientists can create one that has genes for both CD4 and fusin, it may become as susceptible as any human. The new findings still warrant some caution; no one knows how well they’ll hold up outside the test tube, or in lab studies involving different strains of the virus. Berger suspects that HIV may exploit a number of fusin-like receptors. If so, at least resarchers are now on to the game.
