By David N. Leff
Osama bin Laden and HIV ¿ the AIDS virus ¿ are role models for each other. Both killers lie hidden under deep cover. Both are being hunted down by agents of the U.S. government. In the case of HIV, those agents are the National Cancer Institute and its collaborator, virologist Roger Pomerantz, chief of infectious diseases at Thomas Jefferson University in Philadelphia.
Pomerantz is senior author of a paper in today¿s issue of the journal Blood, dated Nov. 15, 2001. Its title: ¿Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART.¿
¿Its main finding,¿ Pomerantz told BioWorld Today, ¿is that we have worked with a group at the NCI to evaluate a drug that stimulates HIV out of latency ¿ out of its hiding position. To look at a new approach, not for treatment but actually viral eradication.¿
He explained: ¿HAART ¿ highly active antiretroviral therapy ¿ is a combination of treatments that are indeed highly active. That means it drives most patients¿ virus in their blood down to undetectable levels. So what we would like to see is people who are on HAART ¿ who have had no detectable virus for many years ¿ getting this drug, prostratin, so we can at least approach the possibility of total viral eradication.
¿The first step, the induction step,¿ Pomerantz continued, ¿is making sure that HAART does its job ¿ getting rid of all the large amount of virus that¿s replicating in the patient¿s blood. If they don¿t flush that out first, then the rest is neither here nor there. The problem with most of this is that HIV, when there¿s some left ¿ and there¿s usually just a little virus left after HAART treatment ¿ does not go anywhere. It can¿t be seen by the immune system; it can¿t be hurt by antiviral drugs. It just lies there fallow, so when you stop taking those HAART drugs, it will emerge from latency and reignite the viral brush fire.¿
Like al Qaeda¿s widely scattered cave refuges, latent HIV holes up, Pomerantz observed, ¿in resting T cells and monocyte macrophages of the immune system, but also in cells that we¿ve shown in semen, possibly in the brain.¿
He and his co-authors have their hopes pinned on a drug called prostratin, which came to light a decade ago. ¿What it does is try to drive the little bit of HIV that¿s hiding in viral reservoirs out of latency,¿ he said, ¿so it can be killed by the immune system and by antiviral drugs.¿
Natural Product Yields HIV Agent
Untold centuries before prostratin got its modern chemical name, natives of Samoa in the Pacific Ocean were brewing a tea from the leaves of a small tree (Homalanthus nutans) growing in the primary Samoan forest. This ethnopharmacological infusion, their tribal healers told U.S. drug discoverers a decade ago, was used to alleviate back pain, abdominal swelling and circumcision wounds; the tree¿s roots to suppress diarrhea; and the stem wood to treat yellow fever.
This herbal remedy reached the war on AIDS via the earlier presidential war on cancer. ¿When the drug discovery group at the NCI, which is mandated by Congress and the president to explore the world for natural products,¿ Pomerantz recalled, ¿got the Samoan bark and isolated its active compound, they started looking at what it did. They thought prostratin was going to be an anticancer agent, but it turned out to be more important for stimulating HIV into coming out of latency. So a year ago they invited me to look into its anti-HIV potential.
¿Prostratin,¿ Pomerantz pointed out, ¿sounds like a typical name of the group of compounds it¿s in, namely, a phorbol ester. Phorbol esters are small molecules that are usually tumor-promoting. What¿s interesting about this one is that prostratin is among the few phorbol esters that are actually tumor-inhibiting. This makes it helpful for what we might want to use it for. In this case it stimulates HIV, which is integrated into an infected cell, to start reproducing.¿
With the NCI baby deposited on their doorstep for adoption a year ago, Pomerantz and his co-authors tackled several questions regarding prostratin. ¿First we tried to reproduce the drug¿s original effects: Does it stimulate HIV out of latency from cell lines? How does it affect T-cell growth and macrophage growth differentiation? Does it inhibit HIV when a person gets acutely infected?
¿And finally,¿ he recounted, ¿we selected six patients from our cohorts of individuals who have had no detectable virus on HAART for long periods of time, but obviously are not cured. When we took their blood cells, we asked whether exposure to prostratin would stimulate HIV out of its latent state in those cells. And we found that it did, in four out of six cases.
¿All this we performed in vitro ¿ in cells,¿ Pomerantz continued. ¿It allowed us to say that now we can use prostratin therapeutically to drive HIV out of latency ¿ on the condition that it proves nontoxic in humans. Right now, we have toxicity studies going on in monkeys for starters, and we¿ll see where that goes. The problem is that viral latency is not as well described in the simian immunodeficiency virus [SIV] primate system as it is in humans. So we hope that prostratin, once it¿s found nontoxic, would permeate and saturate the whole body systemically, and winkle out these viruses from their latency reservoirs.¿
Double Paradox: Wakes Virus, Slays T Cells?
¿What¿s interesting about prostratin,¿ Pomerantz summed up, ¿is that it has two bangs for the buck. It stimulates HIV out of latency but it¿s also an antiviral. It actually inhibits HIV from binding and replicating in a new, uninfected cell. So it adds on to HAART in that way, as an adjuvant. The next step will be to see, after toxicity testing, whether prostratin can be used in humans, and whether people who are on HAART combination cocktails with no accessible virus in their blood, but whom we know were not cured, will go on to this potential drug for viral eradication or long-term remission. That at least,¿ he concluded, ¿is what we¿re hoping.¿