Newsday - June 3, 2001
Laurie Garrett, Staff Writer

The president's comments were echoed in April by Secretary of State Colin Powell in testimony before Congress, in which he said the aim of the administration is to "ultimately find a cure" for AIDS. Health and Human Services Secretary Tommy Thompson, in his first staff briefing at the agency, said, "The best thing that this department can do is find a cure for HIV, and that is the best solution to a lot of our health problems." In mid-May at a luncheon speech at the World Health Assembly annual meeting in Geneva, Thompson reiterated his call for a "cure."

He told the gathering, "Scientists at the NIH [National Institutes of Health] assure me that we will have a vaccine within three to five years."

What is striking about these comments is that few, if any, AIDS researchers speak today of searching for a "cure" -- that word hasn't been part of the epidemic vernacular for well over a decade. And Thompson's optimistic vaccine forecast is stunning to experts in the field, few of whom believe a truly preventive HIV vaccine will be developed and widely available before 2015, if then.

There is, political insiders say, a disconnect within the Bush administration between an apparently vigorous desire to solve the 20-year-old AIDS crisis and the scientific realities that have stymied efforts to prevent HIV infection or destroy the virus in infected individuals -- thus curing them.

Nevertheless, with U.S. basic research funding nearing $2.5 billion a year, it seems reasonable to ask why the Bush administration's call for rapid development of both a cure and a vaccine cannot be realized.

A top U.S. government official, who spoke on the condition that he and his agency not be identified, said the AIDS pandemic, which has sickened or killed 60 million people, is considered grave and has been discussed frequently at cabinet level. The source noted that Powell, in particular, has placed AIDS squarely in the center of U.S. foreign policy, and has frequently addressed the subject with African officials.

"We really are going to be in a leadership position," Tom Novotny, policy adviser to Thompson, said in an interview. "We're going to prioritize this thing. We're committing huge resources to research, to finding a cure and a vaccine. This is a major, major priority for us." Dr. Anthony Fauci, who as director of the National Institute of Allergy and Infectious Diseases has overseen most of the world's basic HIV research, finds the Bush administration's perspective "very, very exciting," he said in a recent interview in his Bethesda, Md., office.

But Fauci hasn't himself uttered the word "cure" since the early 1980s, when scientists realized that HIV was a retrovirus -- a type of microbe that infects cells by copying its own genetic material and then inserting it directly into human genes, the DNA. HIV not only executes this feat of genetic skullduggery, but goes a step further, specifically targeting cells of the very type that are supposed to prevent such occurrences, namely those that make up the immune system.

To cure such an infection would require one of two options: kill every single infected cell in the body and destroy all viruses floating outside of those cells in the human bloodstream. Or, spare the infected cells but destroy the viruses hidden inside human DNA without damaging human genes in the process.

That first option was tried, and, although it has extended lives, it has failed to eliminate HIV or prevent it from developing into AIDS. It is HAART, or Highly Active Antiretroviral Therapy, and when it was introduced in 1996 scientists hoped it would destroy all HIVs as they tried to come out of infected cells. The HAART drugs attack the viruses' ability to make copies of its genetic material by hindering a vital HIV molecule called reverse transcriptase. And they stop a second step -- the packaging of newly made viruses -- by damaging another HIV molecule called a protease. But it turns out HIV is capable of hiding throughout the body in locations not accessible to the drugs, inside immune system cells that are sedentary.

So daunting are these tasks -- so far beyond the current intellectual level of biological sciences -- that the search for a cure effectively ended on the day in 1983 that French scientist Dr. Luc Montagnier announced discovery of the AIDS-causing retrovirus. Science has yet to discover a genuine cure for any viral disease, though it is possible to stop some infections through vaccination. Retroviruses, because of their unique abilities to hide inside human DNA, are even more difficult to tackle than such common viruses as influenza and those that cause colds.

And science has yet to come up with a cure for the common cold.

The administration's call for a cure, though appearing naive, "is a sincere effort to understand the issues," Fauci said. "They are not spouting out "cure', they are asking and probing. They are learning fast and gathering as much information as they can."

Thompson's enthusiastic prediction that an AIDS vaccine will be available within three to five years brought audible groans from AIDS scientists at the Geneva gathering. And it prompted author Jon Cohen, writer of the newly released book "Shots in the Dark: The Wayward Search for an AIDS Vaccine" to recall Thompson's predecessor in the Reagan administration, Margaret Heckler. On April 23, 1984, in an HHS press conference, Cohen said, Heckler predicted that an AIDS vaccine would be "ready for testing in approximately two years."

She was dead wrong.

Seventeen years later, with an estimated 16,000 new HIV infections occurring daily, 77 potential vaccine products have been tested in humans. Only two have reached final Phase III clinical trials, a stage that measures actual efficacy -- and neither of those is considered likely to offer reasonable protection against HIV.

"Most researchers believe that a highly promising ideal vaccine candidate is not at hand, and that it will be necessary to evaluate additional candidates," wrote Dr. Gary Nabel, director of the NIH's Vaccine Research Center, in a recent issue of the British science journal Nature.

Ten years ago, when AIDS research seemed to have stagnated, a boost in funding coupled with a serious restructuring of the NIH's HIV research program brought in a wave of young, bright scientists, and produced an explosion of research that led to development of, among other things, the HAART drug cocktails. Mark Harrington and his Manhattan-based activist organization, Treatment Action Group, played a key role in invigorating the NIH and forcing Congress to increase funding.

"It wasn't just the urgency of AIDS that brought so many smart, young researchers into the field during the 1980s and 1990s," Harrington said in an interview. "It was also the fact that NIH was providing sharply increasing funds for HIV/AIDS research over that period. We've spent about $15 billion on HIV/AIDS research, are at $2.4 billion per year now, and are increasing spending by about $200 to $300 million per year. No other country comes near that amount."

Private sector spending, primarily in the pharmaceutical industry, has also reached billions of dollars, though precise figures are not available.

But with such a high level of funding, and arguably the best-trained biologists in the world engaged in research, the enterprise has not identified an effective cure or vaccine. Why? Newsday posed this question to dozens of the world's top HIV scientists and policy leaders. Their answers reflect a mix of three elements: Irritation over a long list of key questions about the virus and the disease process that have gone unanswered largely, the scientists argue, because of the absence of a well-directed, concerted effort to solve the mysteries.

Intellectual frustration. The scale of the challenges posed by the virus is daunting. Discontent with NIH direction. How the agency goes about directing and funding studies has generated skepticism about how research decisions are being made.

A long list of fundamental questions regarding how the virus infects cells, causes AIDS, eludes the immune system and does, or does not, afflict other animals remain unanswered. Most HIV experts interviewed said those questions dwarf all other HIV research considerations.

It is known, for example, that HIV's closest relatives are monkey and ape Simian Immunodeficiency Viruses, or SIVs. And there is strong evidence that the human viruses arose directly as a result of people's exposures to blood of infected monkeys, probably during the hunting or butchering of the animals for consumption.

Yet, some monkey species and chimpanzees can harbor SIV and HIV without any ill effects. Indeed, two species -- African green monkeys and sooty mangabeys -- can have billions of SIVs in every single drop of their blood without ever showing signs of illness.

Why?

"The question of why green monkeys and sooty mangabeys do not get sick from their SIV is an interesting and relevant one, and one with potential practical implications," Dr. Ronald Desrosiers of Harvard Medical School said. "There is clearly not a problem with the virus; SIV from these species can cause AIDS when used to infect Asian rhesus monkeys."

Something is protecting those African animals -- something that just might be a clue for vaccine development. Yet there has never been an all-out, government-funded effort to find an answer. A hodgepodge approach, taken by various small labs, has failed to resolve the issue.

Nor has there been a directed effort to answer other such critical questions as:

Why do immune system CD4 cells die during HIV infection, leading to AIDS?

How does the virus get inside human DNA, and, once there, force the infected cell to follow its commands, mass-producing more viruses?

Why does the antibody response that follows HIV infection succeed initially in controlling the virus, but eventually fail?

Why can't scientists find people who are naturally immune to HIV, able to get infected yet possessing antibodies strong enough to defeat the virus? (In the mid-1990s, researchers did discover people who are genetically uninfectable because their CD4 cells are abnormal, lacking a protein on the surface that HIV uses to gain entry to the cells. But it turned out that these people are not immune to the virus, because some HIV strains can bypass their genetically aberrant cell receptors.)

What differences might there be between the course of the disease in otherwise healthy, well-fed Americans vs. Africans and Asians who are simultaneously afflicted by a host of tropical ailments such as malaria and parasites?

For more than 12 years it's been known that some sort of chemical is released by immune system CD8 cells to control HIV. It is a powerful compound, or group of chemicals, that acts on the virus in doses so minute it can only be measured with difficulty. What is the substance, and why hasn't it been isolated and identified?

Why do the infection rates vary so widely from country to country? Which social and biological factors play the greatest role in promoting spread of HIV?

There are two types of HIV: the super-lethal HIV-1 that is causing the global pandemic, and its close cousin, HIV-2, which is found almost exclusively in West Africa. What properties does HIV-2 have that make it less virulent? And why hasn't it followed HIV-1's worldwide spread?

Nearly all of the known forms of HIV-1, as well as HIV-2, can be found in New York City. And though New York has the largest number of AIDS cases in North America, none of these viruses -- most of which originated in now-devastated, AIDS-afflicted parts of Africa -- have managed to really take off in the U.S.

What social and/or biological constraints are preventing such a catastrophe?

What role do other, untreated sexually transmitted diseases, such as gonorrhea, play in promoting transmission of HIV?

The key obstacle to solving these, and other long-standing mysteries, scientists insist, is that HIV uses the chemicals normally found in the human body to its advantage, and does so with such exquisite mastery that each step forward in human understanding simply opens up another box of mysteries.

For example: In order for HIV to reach its hiding place inside human or monkey DNA, it must first attach itself to key proteins on the outside of certain types of cells, particularly CD4s. It must latch on to at least three different proteins and, in the process, change its own shape in order to get in. That act involves not only adhering to normal cellular receptors, but also marshaling vital human chemicals floating about the cell's surface.

After attachment comes a sneaky entry into the cell, facilitated with the assistance of human molecules that normally perform other functions. Once inside, HIV must reach the cell's nucleus, get across the nuclear membrane and insert itself inside the DNA -- and, again, each of those steps involves commandeering molecules that normally perform other tasks.

Once HIV is ensconced inside the DNA, its impact is permanent, says Mark Meusing of the Aaron Diamond AIDS Research Center in Manhattan. "Insertion into the genome is covalent and irreversible. So all daughter cells derived from the first one that HIV infected are altered." From then on, every cell in that lineage will contain an AIDS time bomb inside, capable of switching on and turning the cell's entire molecular machinery into an HIV virus-making factory.

The virus accomplishes this feat of cellular hijacking using perhaps fewer than a dozen of its own molecules.

So perfectly evolved is HIV that it can accomplish each step -- cell entry, movement within the cell, insertion into the DNA, replication to make thousands of copies of itself, packaging of those offspring viruses and expelling the progeny into the bloodstream to infect other cells -- largely through manipulation of so-called host factors, or human-made chemicals.

Some of HIV's tricks are ancient ones, shared with hundreds of other types of viruses. Others appear to be unique to the small family of microbes to which HIV belongs, called lentiviruses.

And HIV has a few truly unique tricks.

For example, Jennifer Olvera of the Salk Institute in California has shown that when something goes wrong, and the virus is unable to commandeer host factors necessary to insert itself into human DNA, a sort of traffic jam builds up in the cellular cytoplasm. Like rush hour freeways, the cell's transport systems are clogged with HIVs that are trying, unsuccessfully, to reach the same destination. But even in that seemingly stymied state HIV is still able to promote illness because the cell responds by committing suicide.

Indeed, HIV's apparent fallback position when events do not proceed in its favor is to trigger events that cause the host cell to kill itself, in a process called apoptosis. Further, many steps in HIV's life cycle require the presence of human -- and only human -- molecules. This could explain why monkeys, chimpanzees and genetically modified mice usually don't die of HIV infections.

"So that tells us there's activity present in human cells that's essential to virus activity," the Aaron Diamond Laboratory's Paul Bieniasz said. Even when Bieniasz makes mouse cells with human receptors on their surfaces so HIV can attach, the virus cannot successfully make copies of itself inside those modified mouse cells.

"We still cannot get virus replication" in these altered mouse cells, Bieniasz said. Almost plaintively, he asks,

"Why?"

HIV also has a large bag of tricks for fooling the human immune system. Chief among them, Tufts University molecular biologist John Coffin says, is sugar. The proteins on the outside of HIV "have more sugar on them than any other protein molecule we know of," Coffin explains. So HIV sneaks past immune system sentries, looking like nothing more dangerous than a microscopic M&M candy.

The bottom line from the point of view of cure and vaccine seekers is that there aren't a lot of chinks in HIV's armor that aren't, in fact, human. Drugs or vaccines that aim to closely target given stages of the HIV life cycle will, in fact, be taking aim at human factors that are essential to the functions and survival of all the cells in our bodies. HIV has turned the cell's own chemistry against itself, argues NIH biochemist Alan Rein, more effectively than any other known virus, including its cousin, SIV.

The coup de grace -- HIV's final scheme of survival -- is to change itself constantly. Kathryn McGrath of the University of North Carolina in Chapel Hill has shown that viruses found in the blood of AIDS patients are constantly transforming, probably in response to pressure from the always-fighting immune system. They evolve through at least two mechanisms: Either by combining one virus with another, to produce mosaic versions that immune systems cannot recognize. Or by mutating, altering isolated bits of their genetic material.

And the University of Rochester's Carrie Dykes has recently discovered that the mutation rate of HIV is breathtakingly rapid. About every eight hours a new batch of HIV progeny is made in an infected cell. Up to a third will be recombinants -- those mixed mosaic viruses. And at any given point, or nucleotide, in the virus' genes, the odds are one in 500 that a mutation will have occurred in a given cycle of replication.

In practical terms, this means the immune system rarely sees the same virus at any given time in the course of a patient's infection. These mutants can escape human antibodies.

And, researchers say, the mutants can escape potential vaccines and drugs. Coffin argues that the only way to really tell that an anti-HIV drug is working is to watch for the emergence of drug-resistant mutants, "because, by definition, if something works against HIV the virus will evolve to get around it."

And that's a Catch-22: To kill the virus without in the process killing the host, new drugs or vaccines would have to target those few molecules the virus most desperately needs, and which are part of its own genes -- not the human-made molecules that it commandeers. But HIV is so adept at rapidly mutating its own genes that it is precisely those targets which are the hardest to see and to hit.

"This bodes ill for the future," says Bette Korber, who runs the largest repository of HIV strains in the world, located at Los Alamos National Laboratory in Santa Fe, N.M. "There is no evidence for a slowdown in viral evolution. Which means that [HIV diversity and mutation] will remain a huge issue for vaccine development."

Wayne Koff refuses, however, to let the endgame be an HIV victory. For nearly 20 years Koff has been leading efforts to find a vaccine. In 1987 Koff ran the vaccine effort for NIH. In those days he had a chart on his wall listing a handful of candidate vaccines, none of which had made its way past tiny Phase I clinical trials.

Today Koff is the scientific director for the International AIDS Vaccine Initiative, IAVI, a privately funded research organization. He argues that though there are more vaccine candidates in the pipeline today, none differs profoundly from those first candidates listed on his 1987 chart.

"It's pretty sad, isn't it," Koff said in a recent interview over lunch in a Manhattan TexMex cafe. "It's highly unlikely we're going to hit a home run. We may not even hit a bunt. So what went wrong?

"Its lack of leadership and lack of authority. You're not going to answer the questions we have been asking since '87 unless you make the priorities and push ahead.

We have to answer these questions."

Koff thinks it's high time the NIH take a more deliberate, directed approach to solving the most urgent of the long-standing HIV questions. But NIH is structured in a bottom-up manner: Scientists in laboratories all over the country (and in some overseas collaborative centers) come up with research ideas, write grant proposals and submit them for review by committees of peers.

Those peer review groups rate the applications and, based on their assessment, the NIH sends some, none or all of the money the scientists originally requested. It's a slow, bureaucratic process, open to political infighting between applicants and their often competitive peers seated on review committees. But it's a system most basic scientists prefer to any alternative in which research priorities are ordered from the top.

The latter would relegate labs in universities to pursuing questions they didn't originate.

"This is the classic NIH bureaucratic nightmare that we've known about for years," Harrington says. "Not only are we facing the same questions 20 years into this mess, but we know how to frame them better now. We have old questions and new tools. And where's Tony Fauci [of the NIH] laying out the agenda?"

Fauci, whose agency has overseen most HIV research grants throughout the epidemic, insists the HIV questions will get answered. He argues that new contract mechanisms offer ways to sidestep the standard grants process. Harrington, to the contrary, charges that the NIH "isn't even setting up an infrastructure to answer such questions."

For example, for more than a decade prominent scientists have pleaded with the NIH to create a tissue and blood bank of samples of human and monkey materials infected with HIV and SIV. Such a tissue bank would offer hundreds of pathologists and biologists the means of comparing how the virus damages tissue, where it hides during latency and how drug treatments affect HIV.

Further, they say, if such a tissue bank were constantly supplemented with patient biopsy samples from all over the world, it might be possible to spot clinical trends and see how co-infection with such things as malaria and tuberculosis affect AIDS at the lymph node level.

"We called for that in '95," recalls Harrington. "In 1996 the Levine Committee [of scientific experts assessing NIH's AIDS program] asked for it." But in the end the NIH set up a modest version of the requested tissue bank, accessible only to a select group of scientists.

"So we have nothing," Harrington charges, with evident bitterness.

Perhaps more critical, Harrington argues, is the research monkey supply: "It's drying up."

The best way to test vaccines, and the only way to answer questions regarding how monkeys do, or do not, protect themselves against SIV, is through research on rhesus macaques and other monkey species. But the Merck pharmaceutical company has been buying up most of the world's non-endangered monkey species supply for the company's vaccine effort, and the NIH hasn't created alternative animal colonies. The monkey shortage is so acute, argues AIDS vaccine researcher Harriet Robinson of Emory University, that "even for those of us who work in a primate center you have to be very, very careful how you use these monkeys. It's critical. You just spend a lot of time working to get more monkeys."

Gregg Gonsalves, policy director for the Gay Men's Health Crisis in Manhattan, agrees the NIH has failed to create essential research infrastructures, and cites the clinical side as his top concern. No one is systematically monitoring how people are responding to the HAART drugs since they were introduced widely in 1996. As a result, treatment is a hit-and-miss operation, largely dependent on the physician's personal experience. Side effects and drug toxicities are piling up, reported only haphazardly in medical journals.

Worse yet, Gonsalves charges, virus targets aren't being pursued for drug development. He cites in particular two components of HIV, called vif and gag-RNA polymerase, both of which appear to be less mutation-prone components of the virus' armamentarium.

"We've been asking them to do these long-term clinical effectiveness studies for three years," Gonsalves exclaims. "And there's nothing. So we have to go to AmFAR and say, please, please, do this vif and RNA-ase, please do it!"

And, indeed, privately funded AmFAR, or the American Foundation for AIDS Research, is now underwriting such modest clinical trials.

"I think it's remarkable how, despite the ridiculously small amounts of money we have, we find areas of science that are not sufficiently funded by NIH and put money into them with good results," Dr. Mathilde Krim, founder of AmFAR, says. "The NIH is not goal-oriented. And we are very goal-oriented."

For example, during the late 1980s AmFAR funded a researcher whose grants had repeatedly been rejected by NIH. Using AmFAR money, that scientist discovered that AZT drug treatment of pregnant mice completely blocked HIV transmission to their fetuses. From that discovery sprung what remains the simplest, most vital life-saving innovation in this epidemic: Treat infected pregnant women, and their babies are born free of infection.

AmFAR officially opposed a call during the early 1990s to create at NIH a sort of Manhattan Project for AIDS, in which a large team of scientists worked in a highly directed manner. But now, Krim says, enough of the basics have been done through the grants process. It's time, she said, for a strong leader to step forward and state the scientific mission.

"The mission could be, "Let's cure AIDS, or let's have a vaccine,' but the mission now is, "Let's study the breadth and depth of the virus.' "And maybe now it needs to be more targeted."

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