Originally created 04/30/01

Discovery of HIV hiding place crushes hope of curing AIDS



Will AIDS ever be cured?

The latest research on the resourceful HIV virus that causes the disease suggests a disheartening answer: Probably not.

Just a few years ago, even some of the most sober-minded researchers wondered if the end of AIDS might be near. Perhaps the pills that miraculously changed HIV from a death sentence to a chronic infection would go the final step, they thought, eventually curing the infection by purging every trace of the virus from the human body.

Such talk quickly faded. The new drug cocktails, amazing as they were, could not get rid of the virus. Even if all signs of it vanished for years, HIV was still lurking somewhere. Inevitably it roared back by the billions as soon as people stopped taking their medicines.

Ever since that realization sank in, finding HIV's hiding places has been the goal of a small group of researchers. What they have learned is one of the biggest disappointments in AIDS research.

The fact that HIV is an insidious and resourceful parasite is hardly a surprise. After all, AIDS researchers already understand in lavish detail how HIV latches onto human blood cells, how it oozes inside and kills them. They know the significance of every bump and crevice on the surface of the virus and how these shield it from destruction.

But no basic AIDS discovery in recent times has proved so disturbing as the way HIV burrows in for the long haul.

It has shifted the ultimate goal of AIDS treatment toward something less ambitious. Since eradicating HIV now seems so unlikely - although not everyone has given up - many contend the next best thing will be somehow training the body to control the virus, to help patients live with HIV instead of getting rid of it.

Many of the insights come from the work of Dr. Robert Siliciano of Johns Hopkins University, who regularly tests the blood of about 50 Baltimore AIDS patients, measuring the virus's persistence despite the best treatments.

"What HIV has done is tap into the most fundamental aspect of the immune system, and that is its immunological memory," he says. "It's the perfect mechanism for the virus to ensure its survival."

Perfect because the virus lies silent inside cells that are programmed to do nothing but sit and wait. They are called resting memory T cells. Their only job is to store a record of the germs they encounter, keeping the body prepared for the next time it sees them.

These cells literally are the immune system's memory, so they must survive for a long time. Otherwise we would catch the same diseases over and over. HIV lies inside these sleeping cells, dormant but dangerous. Siliciano believes this means HIV infection will last a lifetime.

The memory cells do die off, but ever so slowly. At the rate he sees in his Baltimore patients, it will take 73 years for them to go away completely. He cannot imagine a way to speed up the process, certainly not with the drugs now available or with anything else on the horizon.

This latently infected reservoir, as scientists call it, is the single biggest obstacle to getting rid of AIDS. "It's the thing that keeps us from curing this," says Dr. Roger Pomerantz of Thomas Jefferson University in Philadelphia.

None of this was obvious in 1996, the dawn of the modern age of AIDS treatment. Doctors watched AIDS patients literally get up from their death beds after taking the newly available drug combinations. Anything seemed possible.

Dr. David Ho of the Aaron Diamond AIDS Research Center in New York City cautiously speculated about eradicating HIV. If the drugs stopped the virus from infecting more blood cells, then the ones already loaded with virus would eventually die off naturally, leaving the body virus free. Perhaps this would take two or three years, he thought.

But in late 1997, another discovery made that seem unlikely. Siliciano and two other teams independently found the virus inside memory T cells. They checked people who had seemingly been free of virus for two years. Every time, they found fully potent copies of virus inside their memory cells.

No one understood then how long these cells would stay alive, although it was assumed it would almost certainly be more than a couple of years.

"It was a sobering realization about the recalcitrant nature of this reservoir," remembers Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases.

The next obvious approach was to try to destroy these Trojan horses.

Fauci's team tried to "flush out the reservoir," as they put it. The idea: Intermittently feed the body interleukin-2, a growth hormone that would make these dormant memory cells awaken and then die.

The experiment seemed to go well. Doctors biopsied patients' lymph nodes and found nothing. They grew hundreds of millions of their cells in cultures. Still nothing. Finally they stopped all treatment and waited. Within three or four weeks, they had their answer. The virus came back in every single patient.

"We are not going to be eliminating this reservoir," Fauci now says. "Whether you can measure it or not doesn't seem to have a significant impact on the clinically relevant phenomenon of what happens when you stop drug."

Nevertheless, scientists have learned much about how the virus hides. HIV's primary target in the body is a kind of white blood cell known as a cd4 T helper cell. The virus infects them, hijacks their machinery so they manufacture more virus, then kills them.

After they get infected, though, a few of these helper cells become memory cells. HIV has already stitched its genes into the cells' genetic code in preparation for making more virus. But nothing happens. The cells go to sleep, virus and all.

All of this happens within the first days of an HIV infection, even before the body begins to make antibodies against the virus. The number of cells involved is relatively small, perhaps 1 million scattered through the blood stream, the lymph glands and perhaps elsewhere.

Normally, the body kills HIV-infected cells. But it misses these, because they look perfectly normal. "The only difference between a latently infected cell and its uninfected counterparts is a little bit of HIV DNA," says Siliciano.

This similarity also makes the infected cells almost impossible to kill with any kind of targeted drugs. There is simply no easy way to sort out the good from the bad.

Siliciano has been counting these cells in his Baltimore volunteers for five years. The number he finds in their bodies now "is essentially exactly the same as they started with."

Why do they die off so slowly, if at all? There are two leading theories: Their longevity reflects the basic biology of memory T cells, or their supply is constantly replenished.

Siliciano favors the first theory. Immunological memory lasts forever. This is why someone who catches measles in childhood will remain immune to the disease into old age.

Memory cells may die over time, but they also make replacements by cell division. And every time a memory cell divides, it faithfully reproduces the HIV that is stitched into its genes.

However, the Diamond Center's Ho prefers the second theory. Actually, memory cells are much shorter lived, he believes. But their supply is constantly being renewed by a continuing cycle of low-level infection.

The standard drug regiments - what doctors call highly active antiretroviral therapy, or HAART - can reduce viral levels by 10,000 fold. But perhaps they do not completely stop the virus from infecting fresh T cells. Some of these go on to become infected memory cells. Thus, however quickly these memory cells die, they are replaced by more.

"If we could stop the residual replication, what would be the persistence of the reservoir?" Ho asks. His team has started a new experiment, code numbered 377, to find out.

They have come up with a new four-drug combination, a kind of super-HAART, that they believe is more powerful than the standard variety. About 30 patients are taking the drugs. The goal is to stop the low-level circulation of their virus, which in turn should shut off the supply of newly infected memory cells.

If it works, Ho believes it could wipe out the body's HIV-infected memory T cells in three to four years.

"No one would say that once we get rid of this reservoir, we have a cure," says Ho. "We have confronted a difficult problem, but there may be others."

Among the biggest of these is the worry that infected memory T cells are not the body's only long-lived reservoir of HIV. The virus may linger as well in other places that are hard to check or lie beyond the reach of AIDS drugs, such as the brain, bone marrow and testes.

"It will be a daunting task to eliminate those unknown viral reservoirs, even with much more potent drugs that might come out in the near future," says Dr. Tae-Wook Chun of the National Institute of Allergy and Infectious Diseases.

This is why Chun and many AIDS researchers now believe the best defense against HIV may ultimately be the body's own.

These doctors would like to teach the immune system to control HIV, so people can stop taking AIDS drugs, which have unpleasant and unhealthy side effects.

No one can say whether this is even possible. But they already can envision a strategy: Shut down viral replication with standard drugs. Then give vaccines and other boosters that will intensify the body's natural - and up to now, failed - surveillance against HIV.

In time, they say, the immune system might learn to do the entire job alone. But all of this is unproven theory, just like the idea of viral eradication was five years ago.

On the Net:

Chun-Fauci article: http://www.niaid.nih.gov/director/pnas/1999/chun.htm