SCIENCE / MEDICINE : REPORT FROM STOCKHOLM : A World Update on AIDS Research
With better drugs and a vaccine against the human immunodeficiency virus still lacking, new diagnostic tests and progress in basic research held center stage at the fourth international conference on AIDS here last week.
The five-day meeting drew more than 7,000 participants from about 140 countries. In a question-and-answer format, here is a summary of some of the key new information presented.
Q:
What developments generated the most interest?
A:
A sensitive new diagnostic test is able to detect HIV infection, even when so little virus is present that neither viral proteins nor antibody molecules can be measured in the bloodstream.
The technique, called polymerase chain reaction, or PCR, has been used to study this apparently rare situation. Dr. Steven Wolinsky of Northwestern University Medical School in Chicago described 15 cases in which virus was measured in this fashion more than six months before conventional HIV tests turned positive.
In 10 of the cases the delay between the first positive PCR test and the first positive “Western Blot” conventional test was between one and two years. In one case, it was 36 months and in another, 42 months.
PCR was pioneered by scientists at Cetus Corp of Emeryville, a Northern California biotechnology firm. It differs from conventional HIV tests because it detects the nucleic acids that make up the viral genes, not viral proteins or the antibody molecules produced by the body in response to HIV infection.
In the still experimental lab test, recombinant DNA techniques and special enzymes are used to make many copies of the nucleic acids contained in an individual’s white blood cells. This “amplified” nucleic acid mixture is then checked to see if it contains gene sequences that match those present in the AIDS virus. Only a small blood sample is required.
“It’s an elegant technique,” Wolinsky said in an interview. “But we need more data before we can say whether it should be used as a screening test for high-risk individuals.”
Among the key unanswered questions are the frequency with which so-called latent HIV infections occur, for example in individuals who have received AIDS-contaminated blood or have had sexual intercourse with infected individuals. In addition, it is not known whether individuals with latent HIV infections are infectious to others. Moreover, it is not known whether the sophisticated technique will have a higher error rate when performed outside of research laboratories.
Q:
Does the PCR technique have other applications?
A:
Yes, researchers hope to apply it to many different viral diseases, as well as perhaps for genetic screening. And because it can apparently be performed on autopsy specimens preserved in wax blocks, it may allow scientists to investigate reports of early cases of HIV infection such as a widely publicized case of “Robert R.,” the teen-ager from St. Louis who died in 1969, who may have been the first AIDS victim in the United States.
Wolinsky has also used PCR to accurately diagnose HIV infections in a group of 17 babies, in one case two days after birth. About half of the babies born to HIV-infected mothers are also infected with the virus. Previously, however, it has been difficult to use conventional AIDS tests to distinguish between infected and uninfected babies. This is because even uninfected babies have AIDS antibody molecules from their mothers in their bloodstream. These antibodies may persist for up to 15 months.
Accurate early diagnosis would allow infected babies to begin experimental antiviral therapies. It would also relieve concerns about HIV infection in those babies who test negative.
Q:
What else has been learned about the virus?
A:
A great deal: About 25% of the more than 3,100 presentations focused on HIV and its interactions with the body’s immune system. More and more mutant AIDS viruses are being discovered.
Particular attention is also being focused on the different immune system cells infected by HIV. At prior conferences, protection of the T-4 lymphocyte, a key disease-fighting cell, has been seen as the key step in preventing the development of immune system abnormalities. Now, this focus has been broadened to include the immune system scavenger cells called macrophages, which destroy invading bacteria and other foreign material.
It has been known for several years that macrophages as well as T-4 cells are infected with HIV. Now macrophages are being more frequently discussed as a bloodstream reservoir for HIV infection. They are also thought to help spread the virus to other organs, such as the brain and the intestines.
Q:
Chimpanzees can be infected with the AIDS virus but they don’t get sick. Have researchers discovered how to mimic the immune deficiency caused by human HIV infection in laboratory animals?
A:
No, but significant progress was announced. A monkey infected with the variant AIDS virus HIV-2 developed life-threatening fungal infections of the brain and lungs, according to Dr. Luc Montagnier of the Pasteur Institute in Paris.
Scientists at the U.S. National Institute of Allergy and Infectious Diseases said that they had developed a partial mouse model for AIDS.
Using recombinant DNA technology, a team led by Dr. John M. Leonard introduced the HIV genes into fertilized mouse eggs and produced mice containing AIDS virus genes in every cell of their body. About half of the offspring of these mice developed AIDS-like symptoms, such as lung infections and enlarged lymph nodes. The mice that became sick died within 30 days of birth.
The mouse disease is not identical to human AIDS. For example, the mice do not have a reduced number of T-4 lymphocytes, as AIDS patients do. And the AIDS virus is contained in each cell, not just a relative few, as in humans, according to the researchers. But these so-called transgenic mice may still have many uses in AIDS research, for example, in testing antiviral drugs.
Because of the potential hazards associated with breeding mice that can manufacture HIV, the experiments are being conducted in a Plexiglas and steel containment area called a glovebox. To prevent mice from escaping, entry to the glovebox is protected by a 40-gallon tank of bleach, steam sterilizing equipment and a series of five doors. Less dangerous strains will need to be developed before such mice can be used easily in research.
Q:
What is the status of experimental antiviral treatments?
A:
There is no convincing evidence to date that any are effective in prolonging the lives of people with AIDS or other HIV-related diseases, according to most AIDS experts.
The latest directory of experimental treatments compiled by the American Foundation for AIDS Research lists 84 drug approaches but many have yet to be tested in humans. Others are still in early stages of clinical testing, designed to determine safety and not effectiveness.
Three of the drugs that attracted wide interest at the conference were soluble CD4, dextran sulfate, and IMREG-I.
Soluble CD4 is a genetically engineered protein designed to block the ability of the AIDS virus to invade T-4 cells and macrophages. It is meant to act as a decoy for the virus by mimicking the site to which it attaches on the surface of human cells. A dozen promising laboratory studies were presented, but CD4 has yet to be tested in humans. (The medication would probably need to be given as an injection underneath the skin.)
Dextran sulfate is a large sugar molecule that is also thought to stop the AIDS virus from invading immune system cells. It is sold in Japan as a blood-thinning anti-cholesterol medication; it is not approved for sale in the United States. But some American AIDS patients have obtained it from Japan for self-treatment.
Dr. Donald Abrams of San Francisco General Hospital has tested the drug for eight weeks on 29 patients in a study to determine side effects. He concluded that the oral medication is “well-tolerated” and said he would soon begin a larger trial to see if it is effective.
IMREG-I is an immune system stimulant that is administered as a shot into the skin. It contains two small chains of amino acids that are the building blocks from which protein molecules are made. It is reported to have no side effects.
Dr. Arthur Gottlieb of Tulane University Medical Center in New Orleans presented data from a six-month study of 141 patients with AIDS-related complex, two-thirds of whom received IMREG-I and one-third of whom received placebo injections. Gottlieb interpreted the study as showing that use of the drug “is associated with a reduced progression to AIDS.”
But a number of leading researchers, who declined to be quoted by name, said they were not convinced by the data presented. The study results, as well as additional data on IMREG-I, are now under review by the U.S. Food and Drug Administration.
Q:
What about AIDS drugs already available by prescription?
A:
Azidothymidine, or AZT, remains the only drug that has been shown to prolong the lives of some patients with AIDS, primarily those who have had the AIDS-related pneumonia called Pneumocystis.
Two key problems with AZT are its high cost, often more than $10,000 a year per patient, and its toxicity. Many patients must discontinue therapy because of anemia and low white blood cell counts.
As a result, AZT research is focusing on ways to reduce the drug’s toxicity, for example, by alternating it with other medications or combining a lower daily dose with doses of other medications. Two combinations that are being evaluated are AZT and acyclovir, an antiviral drug used to treat herpes virus infections, and AZT and dideoxycytidine, a drug that is potent against HIV in the laboratory but which can cause severe nerve pains in some patients who have been treated with it.
Q:
What about drugs for AIDS-related infections?
A:
The most common cause of death in AIDS patients in the United States is Pneumocystis pneumonia. Preliminary data was presented by Dr. Gifford S. Leoung and Dr. A. Bruce Montgomery from San Francisco General Hospital showing that twice-monthly or monthly inhalation treatments with the drug pentamidine can delay repeated bouts of this pneumonia in AIDS patients.
The effect of delaying such repeat lung infections on the overall survival of AIDS patients is not known, because pentamidine has no effect on the underlying immune deficiency state. Nor has the potential additional benefit of combined treatment with both AZT and inhaled pentamidine in AIDS patients been established.
