By Sean Henahan, Access Excellence

VANCOUVER (July 11,'96) The identification of a new receptor protein required for HIV infection could open up a new avenue in AIDS therapy research, report researchers at the XIth International AIDS Conference.

In order for HIV to enter and infect a cell, it must interact with at least two proteins on the surface of the cell. One of these receptor proteins, called CD4, has been known to scientists for some time. A second protein called fusin, however, used by the strains of HIV associated with late-stage infection and overt AIDS diseases, was only recently identified.

Researchers have now identified a second set of cofactors required by HIV for entry into immune cells. A series of these cells surface proteins, called CKR2b, CKR3, and CKR5 have recently been described.

"Discovery of these proteins opens up whole new ways of trying to prevent HIV infection by blocking the virus from getting into the cell in the first place," says Robert W. Doms, MD, PhD, University of Pennsylvania.

"We can isolate viruses from patients now and very quickly find out which cofactors their viruses use. We'll then be able to try to develop agents that will interfere with those interactions that lead to infection," he notes.

The strains of HIV studied by Doms and his team infect macrophage cells and are known as the M-tropic strains. The viruses that use fusin as an infection cofactor are referred to as the T-tropic strains because of their predilection for infecting T cells.

The Penn researchers have also isolated a dual-tropic virus strain called 89.6 that is able to use either CKR5 or fusin as a cofactor with CD4 to enter a cell. All other virus strains studied thus far use one or the other cofactor, but not both. Doms suggests that 89.6 may offer important clues about the well-known propensity of HIV to mutate within the body and about the progression from infection to disease.

The newly identified proteins also function as receptors for several members of a group of inflammatory-response biochemicals called chemokines. The "CKR" designation of the proteins is scientific shorthand for "chemokine receptor." Several of these chemokines, called RANTES, MIP1-alpha, and MIP1-beta, have been shown to have significant antiviral effects in their own right. In the lab, these chemokines are found to suppress the early-stage M-tropic viruses, but not the T-tropic viruses.

This suggests that the body responds to initial HIV infection with these chemokines that block the CKR series cofactors associated with M-tropic viruses. As a result, HIV viruses that mutate to be able to use other cofactors to enter cells would have a survival advantage. The dual-tropic 89.6 strain may represent a transitional type of virus in the evolution of HIV within the body. "By accumulating just a handful of mutations, the virus might acquire the ability to use fusin in addition to CKR5," Doms speculates. "Then it might continue to evolve to the point where it uses just fusin."

"There are many different virus strains, and different viruses can infect different cells. I suspect what will turn out to be the case is that all of these viruses use different combinations of these cofactors. This could explain why some viruses are more aggressive than others and why some people progress to disease much more quickly than other people," he added.

Doms adds that, with the new cofactors in hand, scientists may now be able to develop transgenic research animals susceptible to HIV infection. The availability of such animals could dramatically boost drug-intervention and other studies of HIV infection.

Dom's research appeared in the June 28, '96 issue of Cell.

Related information on the Internet

XIth International AIDS Conference

JAMA HIV Info.

HIV Replication Primer

HIV Pathogenesis

YAHOO AIDS DIRECTORY