A prominent AIDS researcher said Wednesday that he has isolated three chemicals that may be the long-sought naturally occurring inhibitors of the AIDS virus.
Dr. Robert Gallo, co-discoverer of HIV, the virus that causes AIDS, reports in a paper to be published next week in Science that the three closely related chemicals he has isolated from human blood cells may halt the growth of HIV.
A German scientist also reports today in the journal Nature that he has isolated a fourth chemical with the same function.
Such naturally occurring inhibitors have been the subject of an intensive search since evidence of their existence was discovered nine years ago by Dr. Jay A. Levy of UC San Francisco. They are thought to be the reason why some HIV-infected individuals are able to survive for long periods without proceeding to AIDS.
The inhibitors could theoretically be extremely useful for prevention and therapy, said Reinhard Kurth of the Paul Ehrlich Institut in Langen, Germany, who found the fourth inhibitor.
But whether the so-called chemokines isolated by Gallo are responsible for prolonging the lives of HIV-infected victims is a matter of hot dispute.
Levy said that he had already studied the three chemicals discovered by Gallo and concluded that they are not the agent he is looking for in long-term survivors. They are not the right size, are not potent enough or as long-acting as the factor he is pursuing, he said. Kurth also studied one of Gallo's chemicals and said it "didn't work."
Gallo, who is at the Institute for Human Virology in Baltimore--but isolated the chemokines at the National Institutes of Health--responded that the three chemicals he has identified are effective only when they are used together and that Levy never studied them in that fashion--a point that Levy concedes.
Meanwhile, cautioned Dr. Anthony Fauci, director of the National Insititute of Allergy and Infectious Diseases, "we need to be very careful in identifying any of these agents as the natural inhibitor of HIV. . . . There may be many naturally occurring inhibitors."
The mystery of why some individuals infected with HIV survive for 15 years or longer without any obvious signs of AIDS has long intrigued researchers. Most experts have assumed that their bodies produce some unique chemical that blocks replication of the virus so that, even though it establishes a foothold in the body, it is unable to overwhelm all the body's defenses.
In 1986, Levy demonstrated that CD8+ cells (a type of white blood cell) isolated from long-term survivors secrete a chemical compound that does block replication. Although he has since learned a great deal about this factor, Levy has yet to purify and identify it.
For many years, some scientists refused to believe Levy's results and others chose to ignore them. The growing recognition that AIDS chemotherapy is not highly effective and that vaccines remain in the distant future, however, has forced at least some researchers to begin considering his approach and intensified the search for the inhibitor.
Gallo entered the search a year ago, and his approach was substantially different from Levy. Instead of using CD8+ cells from long-term survivors, he began with HIV-infected CD8+ cells from a mix of HIV-positive people and AIDS patients. Using a test-tube assay for HIV replication, he looked for individual cells that secreted a fluid that blocked viral reproduction.
He then grew large numbers of these cells to obtain enough of the inhibiting agent to allow its purification and identification.
Gallo and his team found that the CD8+ cells that blocked viral replication were secreting three previously known chemokines--chemicals emitted by a white cell to attract other cells. Those three were called RANTES, MIP-1 alpha and MIP-1 beta. Individually, each of the chemicals had little inhibitive effect on HIV. But when they were used together, Gallo reported, they were a potent inhibitor.
Gallo has not looked at blood from long-term survivors to see if the three chemokines are present in above-normal concentrations, nor has he studied the agents' effects in animals or humans. The team has started animal safety studies and "if we get favorable decisions" from the Food and Drug Administration, clinical trials could begin within a year, he said.
Kurth used a different approach to identify a chemical called interleukin-16. It appears much less potent than Gallo's chemokines.
Levy is unconvinced. He notes that he has previously found no correlation between levels of these chemokines and HIV inhibition in blood from his long-term survivors. He also noted that the chemokines play no role in the mechanism by which his factor blocks replication.
Critics also noted that Gallo's paper was released at the same time the Maryland Legislature is considering a three-year, $9-million grant to his new Baltimore AIDS research institute.