By David N. Leff

Science Editor

World War II victory in the Pacific theatre is symbolized by an immortal photograph of American troops raising the Stars and Stripes over Iwo Jima island in February 1945. Defending that 8-square-mile speck of land cost the Japanese forces 22,000 killed or captured fighters, and U.S. casualties were nearly as high. It took another half year of savage combat, island-hopping toward the mainland of Japan, before that country surrendered in August of 1945.

But some Japanese soldiers never knew the meaning of the word surrender. For decades afterward, one or more of them straggled out of remote island hideouts where they had holed up, living off the land, awaiting the counter-offensive they knew their emperor would surely order to preserve Bushido - the samurai-warrior code of honor.

There's an almost eerie parallel between this historical scenario and the natural history of HIV - the human immunodeficiency virus. When overwhelmed and almost wiped out by HAART - the triple-drug "highly active antiretroviral therapy" regimen - the few surviving viruses retreat to remote hideouts in the blood and organs of HIV-infected individuals. They never surrender.

Very recent research - not on mice or monkeys but on infected human patients - shows that the AIDS viral burden in an HIV-positive person on HAART may be down but it's never out. (See BioWorld Today, Sept. 28, 1999, p. 1.)

Now a brief communication in today's Nature, dated Oct. 28, 1999, updates and expands this foreboding fact that the virus is all but immortal. It's titled simply, "Re-emergence of HIV after stopping therapy." The report's first author is virologist/immunologist Tae-Wook Chun, at NIAID, the National Institute of Allergy and Infectious Diseases in Bethesda, Md.

"HAART is a very powerful drug," Chun told BioWorld Today. "It can bring down the viral load from a sky-rocketing couple of million copies per milliliter of blood plasma to undetectable levels. Anything below 50 copies we cannot detect by any of the commercial viral-load assays available."

The NIAID team chose two chronically infected adult male patients who had been on HAART for 30 and 33 months, respectively, supplemented by intermittent interleukin-2, an immune system beefer-upper. "In these subjects," he recalled, "we observed both a reduction of plasma virus to an undetectable fewer than 50 copies per milliliter, and a marked diminution of an important viral reservoir - the pool of latently infected, resting [inactive] CD4-positive T cell, which HIV infects. But the question still remained whether levels of the virus would remain low following discontinuation of HAART."

Dropping Therapy Brought Swift Viral Backlash

"The answer, unfortunately, was a resounding 'no,'" Chun stated. "When these two patients stopped their therapy, viral load quickly rebounded. It became detectable in their plasma within three weeks. Also, the pool of resting CD4-positive T cells carrying replication-competent HIV emerged shortly thereafter.

"We could not detect any latent viral reservoirs in those resting T cells," Chun recalled, "so we wanted to ask if eradication of the virus is achieved in those patients. When high HIV numbers came back so rapidly after HAART stoppage, that suggested to us that there could be other viral-sanctuary reservoirs contributing to the plasma viremia, about which we don't know anything."

It looks to Chun "as if a lot of people paid an incredible amount of attention to this latent resting T-cell viral reservoir. And a lot of them wanted to push the idea that this is probably the last obstacle to overcome to achieve total HIV eradication in patients on the HAART schedule.

"They also speculated that some other reservoirs throughout the body, mostly tissue-related, could exist, in lymph nodes, and probably cells of the brain, gut, bone marrow, genital tract and other organs. Our paper proves that at least one viral reservoir - the pool of latently infected, resting CD4-positive T cells - is rapidly replenished with virus once HAART is discontinued."

Chun pointed out, "Now we need to identify those tissue reservoirs, and come up with a strategy that will eliminate the potentially resurgent viruses in them."

That won't be easy.

"We're trying to identify tissue reservoirs," Chun allowed, "but it's going to be very difficult. First of all we would have to perform some sort of surgery to get at them. Take for example, the lymph node. Lymph nodes are pretty small in healthy, HIV-infected individuals. So the number of cells you're getting out of those tissues is a big concern, because it would be best to use the maximal number of cells. That's not going to be possible with biopsy samples.

"Also, in some of the other tissue or organ reservoirs I'm referring to, HAART might not even be able to get access to those infected cells. If a person takes the triple-drug combination regimen as instructed - people who follow their drug-taking schedule and all that - HAART works just fine," Chun pointed out, "but HAART is not going to work on every single viral reservoir."

HAART Can't Extirpate Every Last Virus

"For example," he went on, "I cannot think of any way HAART can impact on those latent, resting CD-4-positive T-cell reservoirs. The reason is that those therapeutic anti-HIV drugs are directed toward actively replicating cells. So when you deal with latent reservoirs, in which there's no activation going on, HAART's not going to work. However, I think it's still important for HIV-infected individuals to stay on the regimen." The two volunteers who underwent the HAART-stopping experiment have since returned to the treatment, and their viral load is again below 50 copies.

Chun made the point, "Obviously, these HAART drugs can penetrate some of the tissues in infected patients, but obviously they can't contain viral replication 100 percent. So it's up to the drug companies to come up with a more powerful drug. Meanwhile," he concluded, "we should think about boosting the immune system in infected individuals so it can, by itself, control the residual viral replication in those other reservoirs."