Key Molecule That Lets HIV Enter Cells Found
After 10 years of intense searching, scientists have identified a key molecule that allows the AIDS virus to infect human cells, a discovery that promises a new approach to treating the deadly disease and that yields insight into why some individuals are apparently more resistant to the virus.
Identification of this “co-factor” should make it possible to develop inexpensive animal models for the disease, thereby accelerating the testing of new drugs and vaccines.
A team of government scientists announced last month that it had identified such a co-factor, which it called fusin, but further research showed that fusin works only with an unusual strain of HIV that is not important in most human infections.
In contrast, the newly identified co-factor, whose identity is announced independently today by five research teams in three journals, plays a role in the vast majority of HIV infections.
The new substance “is likely to be far more significant than fusin for sexual transmission and is probably more meaningful for understanding the disease process . . . in the majority of infected people,” said Dr. David Ho of the Aaron Diamond AIDS Research Center in New York City.
Because of the discovery, “our understanding of HIV infection has leapt forward,” says an editorial in Nature by AIDS specialist Robin Weiss and Paul Clapham of the Institute of Cancer Research in London.
Viruses are incapable of simply passing through the walls of a cell at will to spread their lethal DNA. Instead, they must hijack the cell’s own machinery and subvert it to their own purposes.
Researchers know that HIV hijacks a protein called CD4 on the surface of blood and other cells, using it to bind tightly to the cell surface--the first step in an invasion. But the insertion of the virus into the cell requires the intervention of a second protein, and scientists have been mystified about its identity.
Amazingly, after a decade of searching, five groups have found it virtually simultaneously, a nearly unprecedented accomplishment in biology.
The key to the identification of the co-factor was discovered last year. Scientists found that three cell-signaling chemicals released by white blood cells can block HIV’s entry into their primary target--human white blood cells called T cells.
The chemicals, called chemokines, normally bind to proteins on the cells’ surface, called receptors. If large amounts of chemokines could block HIV infections, researchers reasoned, they must be flooding the receptors that are used by HIV.
This made the chemokine receptors prime candidates for the long-sought HIV co-factor. Working on that assumption, AIDS researchers began intensively studying all of the known chemokine receptors.
The five teams report today that one of those receptors, chemokine receptor-5 or CKR5, is the elusive HIV co-factor. Two of the papers appear in today’s Nature, one in the June 28 Science and two in the June 28 Cell.
Researchers now suspect that a variety of chemokine receptors may play a role in the HIV-infection process, each one being specific for a different strain of HIV. It now seems clear, experts said, that fusin facilitates the entry of a strain of HIV that has adapted to growing in the laboratory but that rarely plays a role in human infections.
Similarly, the two Cell papers report that two other chemokine receptors play a role in infections by other, less common, strains of HIV.
But it is CKR5 that is of greatest interest because it facilitates infections by the strain of HIV that infects more than 95% of Americans who have the virus.
“I think we still have a lot to learn about these receptors and the chemokines, but knowing more about how HIV gets into cells is a useful first step in finding ways to stop it from doing this,” said John Moore of the Aaron Diamond Center, one of the discoverers of the receptor.
It might be possible, for example, to boost production of the crucial chemokines in the body of a person at risk or to give an added dose by an injection, thereby bolstering the body’s ability to fight off an HIV infection. Alternatively, it should be possible to design drugs or vaccines that bind to CKR5 and prevent it from assisting in the virus’s entry.
The discovery should also make it possible to produce inexpensive laboratory animals, such as mice and rabbits, that can be infected by the AIDS virus. Now, only expensive and increasingly rare primates are susceptible to such infections.
Genetic engineers had previously inserted human CD4 receptors into white blood cells from mice, but these mice are still very difficult to infect. Experts are hopeful that inserting CKR5 along with CD4 will enable them to readily infect the animals. They could then be used for testing experimental drugs and vaccines.
Most intriguingly, the discovery may help to explain why some individuals, such as certain prostitutes and spouses of AIDS victims, do not become infected with the virus despite repeated exposure. Experts speculate that these people produce unusually large amounts of the crucial chemokines, thereby rendering themselves immune. Teams are studying such people now to see if that is the case.
