By David N. Leff

Eric Robert Rudolph, 32, is on the FBI's list of the ten most wanted criminals at large in the U.S. He is charged with multiple bombings of abortion clinics and at least one gay lounge, plus the death of a woman in bombing a park at the Olympic Games in Atlanta. The FBI has posted a $1 million dollar bounty for Rudolph's apprehension

That won't be easy. For well over a year, a small army of federal and local law enforcement agents, plus amateur bounty hunters, have been scouring the rugged brush-covered mountain terrain of western North Carolina, where Rudolph - an accomplished outdoorsman and survivalist - is reliably known to be hiding. High on the world's most-wanted list is a killer that's also adept at hiding out between its death-dealing sorties. The reward money spent on bringing the AIDS virus to book is counted in the billions of research and development dollars.

One of its hard-won successes is HAART, the now-famous triple-drug regimen that sharply curbs the replication of HIV, the human immunodeficiency virus, and halts its potentially fatal infection. HAART stands for "highly active retroviral therapy." It usually consists of two HIV reverse transcriptase inhibitors, plus a protease inhibitor.

No Free Lunch For HAART

But HAART's life-saving track record exacts a ransom. "The drugs are extremely expensive; the cumbersome number of pills to take daily disrupts a patient's life, and there are health-related side effects of the combination therapy," pointed out virologist/immunologist Tae-Wook Chun.

No wonder so many HIV-positive people abandon the demanding regimen, once they begin feeling better. Then the virus promptly rebounds. This compliance erosion led Chun and his colleagues at the National Institute of Allergy and Infectious Diseases (NIAID), to mount a limited patient trial testing a hypothesis they had as to why HAART alleviated, but never cured, HIV infection or AIDS.

It's based, paradoxically, on the cytokine interleukin-2 (IL-2), which stimulates the expression of HIV from the T cells in which it holes up between bouts of infection. A current controversy rages over how long these sleeper viruses can survive in their well-hidden safe houses.

"I can tell you," Chun told BioWorld Today, "that these latently infected cells hide and survive a lot longer than we originally expected. Originally, it was proposed that the half-life of these cells was less than 14 days. But clearly that's not the case. They can survive a long time, and it's problematic because HAART has no immediate impact on this latency reservoir.

"So, that's the reason we were testing this hypothesis of flushing HIV out of latently infected cells," Chun said. "It is widely accepted that probably the only way you can get rid of this virus is by activating latent cells, letting them produce virus, then letting those T cells die." (See BioWorld Today, July 21, 1998, p. 1.)

So, the NIAID group singled out 26 HIV-positive patients of whom 12 were on HAART alone, while 14 took their triple-drug regimen daily plus IL-2 injections intermittently. The purpose was to see what effect the virus-stimulating cytokine had on eradicating the IL-2 group's latent-virus cells. Their report appears in this month's Nature Medicine, dated June 1999, titled: "Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-infected patients receiving highly active anti-retroviral therapy." Chun is the paper's first author; Anthony Fauci, director of NIAID, its senior author.

"In the blood of the cohort on HAART plus IL-2," the paper summed up, "the size of the pool of resting T cells containing replication-competent HIV was significantly lower than that of patients receiving HAART alone. Virus could not be isolated from the peripheral blood CD4+ T cells in three patients receiving IL-2 plus HAART."

"This is the first time," Fauci pointed out, "that we have been unable to isolate replication-competent virus from large numbers of cells from peripheral blood or lymphoid tissue of HIV-infected individuals. However, this does not prove that virus has been eradicated in these individuals."

Chun explained why.

"Those results have important implications in terms of projecting whether eradication is possible, at least in this latently infected T cell compartment," he said. "We are not talking about other body reservoirs of HIV latency. There's no way you can find some of them, because they are hiding throughout the tissues of the infected people."

He spelled out some of these viral refuges: "We know there are a lot of lymphocytes around the gut and testes. People have been talking about cells associated with the eye, and HIV-infected macrophages in the brain; the heart, where drugs cannot access; you name it."

Chun made the point that going after these and other far-flung latency reservoirs, "is going to be very difficult, because lymph-node biopsy is bad enough. It involves surgery to pick up a lymph node, and multiple biopsy is very difficult for patients." He suggested a purely theoretical strategy.

"One way you could probably get around that is identify a person who's just died, and had been receiving HAART for a long time," he said. "Then, [you could] do an autopsy on that patient and try to pinpoint where different HIV reservoirs can be identified throughout the body. Feasibility or common sense tells us that to examine every inch of the body is just not possible.

"And we do know," Chun went on, "that other body HIV reservoirs may exist. What is not clear is that for some of the most difficult parts to reach in the body, we have not enough data to talk about the impact of HAART - whether this triple combination therapy can surely reduce the viral load in hard-to-reach viral reservoirs."

Much Larger, Randomized Trial In Planning Stage

The Nature Medicine paper points out repeatedly that the proof-of-principle trial it reports was non-randomized, hence of purely suggestive significance. Now, its co-authors are planning to follow up with a larger, more valid patient study.

"We want to do a longitudinal trial in randomized fashion," Chun said. "We will look at many patients and randomize them into two groups. All of the patients are receiving HAART to begin with, and we will give IL-2 to half of them. We will try to measure how many latently infected cells are present in each group.

"For the present," Chun concluded, "the bottom line of this preliminary trial is that, unless some dramatic antiretroviral therapy comes along, the best bet is to stay on the HAART regimen for life."

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