A War of Attrition With Virus
A quarter-century after the beginning of the AIDS epidemic, the rapid pace of scientific discovery has slowed to a crawl.
The early years of the epidemic were a sprint, as researchers isolated the virus that causes AIDS, developed rapid tests for the virus and found drugs that could block its replication -- culminating 10 years ago in the introduction of drug cocktails that made long-term survival possible.
Researchers were confident that an AIDS vaccine -- perhaps even a cure -- was just around the corner.
But that optimism evaporated as scientists began to untangle the mysteries of a virus far more intractable than any they had encountered before.
At least 96 U.S.-sponsored vaccine trials are underway, but experts agree that none is likely to yield a useful product.
Potential vaginal microbicides, which would allow women more control over their own risk of infection, remain out of reach.
Although new drugs are entering the marketplace, they are the result of old research.
“The low-hanging fruits have all been picked ... and we still face huge challenges,” said Dr. David Ho of the Aaron Diamond AIDS Research Center in New York.
“This is not because of a lack of effort or because of a lack of money. It’s just a fundamental problem posed by HIV.”
Federal funding for HIV/AIDS research and treatment has grown from $200 million in 1985 to $21.7 billion this year.
UCLA’s Dr. Andrew Saxon, one of the first to report the observation of the new disease 25 years ago, on June 5, 1981, added: “I don’t think anyone appreciated how clever and difficult this virus could be.... I thought we would have had a vaccine by now and we would be entering the age of forgetfulness” about AIDS, just as the world has with smallpox and polio.
International agencies have been making strides in bringing drug therapy to poor areas and in developing prevention tools, but when it comes to fundamental research, “frankly, there isn’t much new,” said Dr. Jay Levy of UC San Francisco, who has studied the disease since it was identified.
“Aside from the terrible spread of the epidemic, there is simply not much news on the horizon.”
World’s No. 4 Cause of Death
In the United States, more than half a million people have died from complications arising from AIDS since 1981, and an estimated 15,000 will die this year, according to the federal Centers for Disease Control and Prevention. More than 1 million people in the U.S. are living with the virus, and 40,000 become infected each year.
The character of the epidemic has changed as well. A disease that once primarily struck gay white men and intravenous drug users has now largely become a plague of the poor and black.
African Americans, who make up about 13% of the U.S. population, account for half of new U.S. infections and a third of deaths. Black males are seven times as likely as white males to be infected with HIV; black females are 20 times as likely to be infected as white females.
Worldwide, the numbers are grimmer.
At least 25 million people have died from AIDS, and 2.8 million will die this year, according to the World Health Organization.
An estimated 38.6 million people carry the virus, and an additional 4.1 million are infected each year in what Dr. Kevin Fenton, head of AIDS programs at the CDC, called “one of the deadliest epidemics in human history.”
The infection rate has slowed in a few countries, but population growth continues to fuel a rise in the number of total infections, according to data released last week by UNAIDS.
Only heart disease, stroke and respiratory infections kill more people worldwide each year.
“It is difficult to reflect back on the last 25 years, to understand how something that began so slowly and quietly and silently can now be the No. 4 cause of death in the world,” Fenton said.
The epidemic has changed the world, making sex an activity to be feared, ruining the economies of many countries in sub-Saharan Africa, leaving millions of children parentless -- and often infected themselves -- and draining billions of dollars that could have been spent alleviating other afflictions.
“We are the last generation to know what life in a world without AIDS was really like,” said Dr. James Curran, who was among the first at the CDC to study the disease and is now dean of Emory University’s Rollins School of Public Health.
A Virus That Lies in Wait
Technically, AIDS has been around a lot longer than 25 years.
The human immunodeficiency virus is a mutated form of an ape virus that has presumably infected chimpanzees and other primates for possibly thousands of years. Most researchers believe the virus mutated and crossed into the human population from close contact between the two species, perhaps when hunters captured and ate the animals.
Genetic comparisons of all AIDS strains collected around the world, performed by geneticist Bette Korber at the Los Alamos National Laboratory, show that the jump occurred about 70 years ago, most likely in Cameroon. People have been dying of AIDS in Africa for the better part of a century, but scientists weren’t aware of it until Americans began to succumb.
In early 1981, Saxon and Dr. Michael S. Gottlieb at UCLA, along with others in Los Angeles, began to see sporadic cases of an unusual form of pneumonia caused by a fungus, Pneumocystis carinii. That rare pneumonia had previously been observed only in patients with immune systems ravaged by leukemia. None of the new patients had cancer.
People elsewhere around the country were also seeing the infections, but UCLA was in a unique position to understand the disease because immunologists Dr. Howard Schanker and Dr. Robert Schroff were studying a kind of immune cell called a T cell.
“Nobody else [in the country] was measuring T cells,” Saxon said. But when Schanker and Schroff measured white blood cells in the pneumocystis patients, “they were dramatically off the wall. It was a big wow!”
An extremely low concentration of the T cells now known as CD4 cells is considered the defining characteristic of AIDS.
The team rushed their findings into print, publishing an announcement in the CDC’s Morbidity and Mortality Weekly Report that five gay men had been observed with an unusual form of pneumonia and severely impaired immune systems.
A month later, CDC researchers reported 24 cases of a rare cancer called Kaposi’s sarcoma among gay men with impaired immune systems.
In 1983, Dr. Robert Gallo of the federal National Cancer Institute and Dr. Luc Montagnier and virologist Francoise Barre-Sinoussi of the Pasteur Institute in France reported that the disease, by then called acquired immune deficiency syndrome, was caused by a retrovirus.
Like many other viruses, the genetic information of retroviruses is encoded in RNA rather than the DNA found in human cells. Unlike other RNA viruses, however, the AIDS virus is able to insert its genetic information into the genome of the cell it infects.
Researchers were woefully unprepared for the discovery, Saxon said. “You could count on your thumbs the number of antiviral drugs available,” he said. Researchers “hadn’t really dealt with retroviruses before HIV. They were medical curiosities that only caused rare diseases.”
The problems that bedeviled researchers then are the same as now.
The main obstacle is the virus’ ability to integrate into CD4 cells, which normally orchestrate the body’s immune response to an infection. “HIV is a finely tuned guided missile” that attacks the core of the immune system, said Dr. Warner Greene of the UCSF Gladstone Institute of Virology and Immunology.
Drugs in the bloodstream can kill off all the virus floating freely, but they can’t touch the virus inside the immune cells. Inevitably, those hidden viruses reemerge.
When the virus mutates slightly, as it has an astonishing propensity to do, it escapes from the cells and starts a new round of destruction.
“In the whole history of vaccinology, in the whole history of virology, this is the first virus that can do that,” said virologist Frederic Tangy of the Pasteur Institute.
The key for a vaccine would be to intercept all invading virus before it could attack CD4 cells -- a “sterilizing” vaccine.
But researchers don’t know how to do that, Greene said.
HIV has a coat of sugars and frequently mutating amino acids that effectively hide it from antibodies that would destroy it. “It’s almost like you are watching a ‘Star Wars’ force shield protecting a station,” said Dr. Ho of the Aaron Diamond AIDS Research Center.
Researchers do not know how to break through that barrier.
“We will not have [a vaccine] in the foreseeable future,” Ho concluded. Vaccines now being tested will help point them toward better ones, but none is likely to help stop the spread of the disease, he said.
The mutability of the virus is also a major impediment to drug treatment.
Twenty-five drugs are approved for treating HIV infections, but some patients have grown resistant to virtually all of them. Nationwide, about 15% of HIV-positive people are resistant to the majority of the drugs, and in Los Angeles County, 21% are, said Brian Risley of AIDS Project Los Angeles.
New drugs can often overcome that resistance -- at least temporarily -- but it is a constant race to stay ahead of the curve, he said.
Drugs are not going to be the long-term answer in any case, said UCSF’s Levy. “These drugs are toxic and have to be taken for a lifetime,” he said. “We couldn’t do that with chemotherapy for cancer, and I am not sure that we can for HIV.”
Levy and others have been looking for naturally occurring chemicals, called chemokines, in white blood cells that give a few people an innate immunity to HIV. “Nature has revealed to us situations in which people have survived the infection, and we have to learn from that,” he said.
But he has been trying for the better part of the last quarter-century to learn how nature does that, so far without success.
Some Bright Spots
Despite the gloom about fundamental research, there is some positive news, particularly about drugs and prevention.
The antiretroviral drug “cocktail,” which 10 years ago was 20 or more pills a day, is now down to two or three. A new combination drug, expected to be approved by the Food and Drug Administration this year, will combine three drugs into one daily pill.
The FDA is also expected to approve a new member of a class of drugs known as protease inhibitors, which were introduced a decade ago and made long-term survival possible. Darunavir, also known as TMC114, differs in structure from other protease inhibitors, and clinical trials indicate it will overcome the resistance problems associated with those drugs.
The company that makes darunavir -- Tibotec Inc. of Yardley, Pa. -- has a drug called TMC125 in an early phase of testing. It may overcome resistance in the class of drugs known as reverse transcriptase inhibitors. And Merck & Co. makes MK-0518, an experimental drug completing human testing that blocks an enzyme used by the virus to replicate inside cells.
Earlier this year, Dr. Thomas Quinn of Johns Hopkins University in Baltimore reported encouraging results on the effects of circumcision on AIDS transmission in a study of 12,000 men in Uganda. The effects of circumcision on AIDS transmission have been a controversial topic, with several small studies yielding conflicting results.
Quinn’s team found that circumcision reduced the risk of HIV infection by 50% in men overall and by 70% in those at highest risk -- although how it does so is not yet clear.
“If we were getting those kind of results with a vaccine, we would be pouring money into it to rush it into use right away,” said Dr. Kevin M. De Cock, director of the World Health Organization’s Department of HIV/AIDS.
Similar trials are now proceeding in two other African countries, De Cock said, and preliminary results could be available by the end of the month.
In the absence of a vaccine, drugs might be used for prevention.
Monkey tests reported this year indicated that a combination of the drugs tenofovir and emtricitabine, sold together as Truvada, blocked new infections when given daily -- even when the animals were exposed to very high doses of HIV.
Safety and efficacy trials are in progress in the U.S., Botswana and Thailand. Some physicians are now prescribing Truvada to high-risk patients.
De Cock, for one, is confident that the pace of research on the virus will pick up again.
“In the 25 years of the history of AIDS, there have been surges of progress in one area of science, then later in another,” he said. “That’s just how it goes.”