Multiple doors for HIV to enter cells

 Just last month, scientists triumphantly announced that they had identified fusin, a protein on the surface of immune cells that some strains of the AIDS virus use to gain entry to the cells. Now, in a discovery that offers an explanation for why some people exposed to the virus remain uninfected, several research groups report that the HIV most commonly found in people actually infects via CC-CKR-5, a different protein on the surface of immune cells.

 The HIV that requires CC-CKR-5 "is the kind of virus transmitted during sex. It's the kind of virus transmitted in 90 to 95 percent of cases and the kind of virus that predominates in people for many years," says John P. Moore of Rockefeller University in New York.

 Like fusin, CC-CKR-5 is a receptor, a protein that normally binds to extracellular molecules and transmits signals into the cell.

 Though investigators don't know what molecules fasten onto fusin, they do know that CC-CKR-5 binds chemokines, proteins secreted by immune cells to attract other immune cells.

 As it turns out, CC-CKR-5 is the receptor for RANTES, MIP1-alpha, and MIP1-beta, chemokines already attracting the attention of AIDS investigators.

 Last year, a group led by Robert C. Gallo and Paolo Lusso of the University of Maryland's Institute of Human Virology in Baltimore described test-tube studies indicating that secretion of these three chemokines by immune cells can suppress HIV.

 More recently, investigators headed by Rockefeller's William A. Paxton reported in the April Nature Medicine that some homosexual men who are HIV-negative despite frequent sexual exposure to the virus generate greater than normal amounts of the three chemokines. Similar results are emerging from a study of hemophiliacs who remain uninfected despite having received HIV-contaminated blood, says Gallo.

 Taken together, these results suggest that the binding of chemokines to CC-CKR-5 can sometimes prevent HIV from infecting a person, investigators contend. To do this, the bound proteins may physically block the virus' access to CC-CKR-5 or they may signal a cell to remove such receptors from its surface.

 At least three different research groups have recently linked HIV's ability to infect immune cells to CC-CKR-5. Rockefeller's Tatjana Dragic and her colleagues, including Moore and Paxton, describe their results in the June 20 Nature. That issue contains a similar report by HongKui Deng of New York University Medical Center in New York and his coworkers.

 The third report on CC-CKR-5, scheduled to appear in the June 28 Science, results from a collaboration headed by Philip M. Murphy and Edward A. Berger, both of the National Institute of Allergy and Infectious Diseases in Bethesda, Md. Berger's group reported the discovery of fusin last month.

 One line of evidence presented by all three research groups is that the addition of CC-CKR-5's gene to HIV-resistant cells that do not normally manufacture the receptor can make the cells susceptible to the virus. Small differences in the proteins that make up the outer surface of HIV determine whether a particular strain depends upon fusin or CC-CKR-5, say investigators. The lab-grown HIV strains used to identify fusin differ from those usually transmitted between people, but they resemble the viruses that emerge in some people after years of infection, says Moore.

 Berger speculates that HIV's evolution into fusin-dependent strains may mark an important transition in the progression of an infection, perhaps signifying that an HIV-positive person will soon start showing signs of AIDS.

 The body's production of RANTES, MIP1-alpha, and MIP1-beta may actually spur HIV to use proteins other than CC-CKR-5, notes Robert W. Doms of the University of Pennsylvania Medical Center in Philadelphia.

 Doms' group has found at least one HIV strain that can infect cells using either fusin or CC-CKR-5. The group also has evidence that some strains can use other, still-unidentified proteins. "It's going to become quite complicated," predicts Doms.

 Both fusin and CC-CKR-5 present tantalizing targets for drugs that would deny HIV access to cells, researchers agree. Yet disrupting the normal role of these receptors-their binding of chemokines-may prove as dangerous as the AIDS virus itself, the investigators caution.

"Since these are normal cellular proteins, you have to worry about what side effects you will get by interfering with them," observes Berger.