Tracing AIDS to Its Last Hiding Place
Researchers are beginning to make some strides toward attacking the AIDS virus in its last hiding place in the body, the hitherto impregnable forts of the immune system, where HIV safely hides from the bomb bursts of combination therapy.
Scientists in California and elsewhere are attacking these redoubts with new vigor because they know that HIV-positive people can never be weaned from toxic, expensive AIDS drugs until the last viral troops are scourged from the body.
A handful of immunologists reported preliminary success this week in Geneva at the 12th World AIDS Congress. One team found that gene therapy can marshal the body’s own defenses to strike at the hidden foe. Other scientists are using new drugs in an attempt to achieve the same goal, while others are poised to launch therapeutic vaccines and synthetic antibodies at the target.
Although none of these approaches is going to produce an immediate cure for HIV infection in the near future, research reported here makes it clear that efforts to stimulate the immune system represent the third great wave in AIDS therapy, after AZT-like drugs and the protease inhibitors.
Reports at the gathering of side effects and poor adherence to “cocktail” therapies have increased the researchers’ sense of urgency.
“It’s very difficult for patients to stay on combination therapy indefinitely,” said Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases. “We need to deal with these viral reservoirs, and deal with them in a creative way.”
The eventual “cure of HIV infection is not a myth,” said Dr. Roberto Siciliano of Johns Hopkins University. “It is a problem we can tackle.”
Combination therapy incorporating the hot new class of drugs called protease inhibitors has shown the remarkable ability to reduce the quantity of HIV in the blood below detectable levels in the vast majority of patients who are able to tolerate them.
But even in the most successful treatments, HIV-infected white cells continue to lurk in lymph nodes, tonsils and the gastrointestinal system, among other places. These cells, called memory T-cells, lay dormant until they are stimulated to venture back out into the blood, a process called activation.
HIV continues to replicate in these sites, said David Ho of the Aaron Diamond AIDS Research Institute, but it does not grow resistant to drugs--indicating that the drugs do not enter the hideaways. Devising drugs that could sneak into the nooks and crannies would be the obvious way to attack the memory cells, but researchers have no idea what keeps the drugs out and thus no clues about how to get them in.
Perhaps the most promising way to attack the memory cells involves a form of gene therapy devised by researchers at Cell Genesys in Foster City.
They isolate CD4 and CD8 white blood cells--the so-called helper and killer T-cells--from a patient and treat them with a harmless, genetically engineered virus that teaches the cells how to recognize HIV-infected cells. The cells are then grown in the laboratory for 10 to 14 days to increase their numbers by a thousandfold or more, then infused back into the patient.
In a preliminary experiment, Dr. Robert E. Walker of the National Institute of Allergy and Infectious Diseases recruited 30 sets of identical twins, one of whom was HIV-positive and one not. He took white cells from the healthy twin, treated them with a marker gene that had no therapeutic value, and infused them into the infected twin.
He reported here that the cells survived for at least 100 days, and that they even proliferated. “This was an unexpected finding,” he said. Most people expected that the infused cells would be cleared from the body rather quickly.
Biopsies by Dr. Peter Anton of UCLA showed that the engineered cells also passed freely into the protected compartments.
Continuing Experiments
Based on those findings, Walker has recently begun a phase two trial in 40 patients whose HIV levels in the blood have been suppressed below detectability by combination therapy. In four of the first five patients treated, said Cell Genesys President Dr. Stephen Sherwin, “we are seeing a trend toward a decrease in HIV” in the reservoirs in lymph tissues.
Ho is ready to try two related experiments in patients with suppressed viral concentrations. In one, he will inject them with an AIDS vaccine designed by Pasteur Merieux Connaught. In the second, he will use a specially prepared antibody that attacks another type of white cell called CD23. In both cases, the hope is to activate the memory T-cells so that they shift into a form that can be attacked by both the body and drugs.
“We are ready to go,” he said.
Immunologist Charles Rinaldo of the University of Pittsburgh is extracting another type of immune cell called dendritic cells. He told researchers here that exposing the dendritic cells to proteins from HIV and to an immune system component called interleukin-12 trains the cells to attack HIV-infected cells.
Similar approaches using dendritic cells have proved useful in preliminary experiments aimed at attacking cancer. Rinaldo said he will test the approach in monkeys later this year and could proceed to human trials in the next two or three years.
The immune system can also be coaxed into attacking cells infected by HIV and other opportunistic infections associated with AIDS. Dr. Brian Herndier and Dr. Michael McGrath of UC San Francisco have been testing a drug called WF10, developed by OXO Chemie of South San Francisco. WF10 has been approved in several countries for speeding the healing of wounds, but Herndier and McGrath found in the laboratory that it could stimulate macrophages, another immune cell, to attack bacteria, fungi and infected cells.
The Food and Drug Administration has been reluctant to allow tests of WF10 for fear that activated oxygen released by the drug would destroy red blood cells. But McGrath reported that when researchers injected the drug into 18 HIV-positive patients whose viral levels were suppressed, they found the drug “completely safe,” with no side effects. More important, it reduced blood levels of a cell called CD28. High levels of CD28 are generally considered a marker that viral levels will rebound, so the decreased levels hint that WF10 is stimulating memory cell destruction.
The UC San Francisco scientists will also begin testing the drug in end-stage AIDS patients because the drug stimulates macrophages to attack aspergillosis and other bacteria that are typically the cause of death in AIDS patients. By interfering with opportunistic infections, the drug could keep patients alive longer.
Finally, a team at the University of Texas Medical Branch at Galveston is studying glycyrrhizin, a drug found in licorice root. Dr. Fujio Suzuki told the conference that tests in immune-deficient mice showed that glycyrrhizin could increase natural resistance to Candida albicans and Cryptococcus neoformans, two fungi that often cause death in AIDS patients.
Glycyrrhizin has been approved for use in Japan for 30 years for treating chronic hepatitis and other viral infections, as well as leukopenia, a condition marked by abnormally low blood cell counts. It has never been used in the United States, but the Texas researchers hope to begin testing it in people soon.
