It's a HAART-less, cruel deception that the now-popular drug therapy against HIV, the AIDS virus, works so well that it may be life-threatening. Here's the paradoxical scenario: An HIV-infected patient, male or female, is prescribed a confusing quantity of antiretroviral pills aimed at reducing the virus from a perilous thrust toward AIDS down to a low, manageable blood level that keeps HIV safely on the reservation.

But it's asking a lot of the patient to remember when to take his medicine, in what order, and in relation to waking, eating and sleeping. Near-perfect compliance not only wards off AIDS but abates the many severe symptoms of HIV infection. "Great!" the patient thinks. "It's working so well I can give up this regimen - at least for a few weeks or months."

HIV may be down but it's never out. Within a few weeks or months - sometimes years - experience shows, HIV has made a comeback. Symptoms have returned, virus in the blood has climbed alarmingly. The AIDS virus re-emerges when the HAART threat has gone away.

"Current opinion holds," suggests immunologist/virologist Simon Swingler at the University of Massachusetts in Worcester, "that HIV's infective particles enter and infect the immune system's CD4-positive cells. This is the first target reservoir the virus centers in its cross-hairs to disable the body's immune defenses."

Swingler is lead author of a report on this subject in Nature dated July 10, 2003. Its title: "HIV-1 Nef intersects the macrophage CD40-ligand signaling pathway to promote resting-cell infection." Its senior author is Mario Stevenson, UMass professor of molecular medicine.

"Probably, our finding suggests," Swingler observed, "that HIV latency is not necessarily dependent on where the virus is but on the activation state of the cell where its reservoir is located. A lot of people," he continued, "decided that it could be a physical compartment that is not accessible to drug therapy. HIV is involved so it can hide itself in plain sight."

How HIV Manipulates Immune System

"The mechanism it uses to do that," Swingler went on, "and how it manipulates the immune system, uses a pathway that nobody expected. Previously everybody understood that HIV replicated in actively cycling T lymphocytes. Whereas we show that the T cell only has to be in the very first phases of the cell cycle to become infected and produce viral proteins.

"And then once it's initiated into full activation it will produce complete particles, so it can hide itself from immune surveillance and yet be present. It's really the molecules involved in both the release from Nef-infected macrophages and how they affect antigens on macrophages. B cells, in turn, change the activation state for a fully or restricted productive replication.

"The prior dogma had two schools of thought," Swingler told BioWorld Today: "The HIV-infected T cell yet reverts to a complete latent state where there are no RNA transcripts from the viral genome and the proteins they made. Or they could infect a compartment, yet replicate at a low rate turnover so the particles are continuously reinfecting cells. We're showing that either of those soluble proteins can become fully activated at relatively high site of origin. They just sit in this viral reservoir, make these proteins and transcribe their RNA."

Does Swingler's finding then suggest that the antiretroviral therapy regimen, which is such a great hope now, must be a life sentence? Does the patient who is now staving off the HIV infection dare not to stop? "That is true," he commented. "Regardless of what we actually found in the cell cycle, that HAART effect has always been true. Our Nature paper really explains where else to look to target virally infected cells, and may suggest ways to get at the virus. Treating the patient with the antiretroviral load down to these set points. That's where it comes to two schools of thought. Now it comes down to three. Where you have a low turnover the virus cells, restricted by their cell-cycle position, are infected. And getting to those cells is the problem."

The crux of the HIV's virulence is a gene called "Nef."

Nef, Swingler explained, stands for "Negative Factor of viral replication. It was thought when the virus was isolated and grown in early tissue-culture days in the late '80s that if you removed the Nef gene, the virus replicated better. It was found out later that starting to use the virus in primary human cells and in animal models, progression to disease was very much a factor when Nef was present. If Nef was damaged or deleted," he went on, "you got a group of long-term nonprogressors, infected but tending not to progress to full-blown AIDS. The Nef genes, it's now understood, represent the more rapid pathogenic determinants of HIV infection in AIDS."

How To Eradicate Nef Gene?

Swingler points out that "most of the things to look at now would be figuring out how Nef orchestrates its signaling mechanism within a macrophage - and preventing it. That's certainly one area that we are trying to interfere with. We could try to move outside and work on neutralizing those soluble factors produced by macrophages. So the three cell types that we studied further were the macrophage, the B cell and the T cell, hopefully for any type of therapy.

"We found that infected macrophages expressed their release to chemokines. Nef induced release of chemokines sufficiently to allow these resting, latent cells to also become infected with HIV. These attracted purified T lymphocytes toward infected macrophages, expressed sufficiently to allow these resting latent T cells to also become infected with HIV. They had the same effect as expression of Nef, and were up-regulated from the same family of kinases, NF(k)B. So the T cells cycled from G-zero to G-1 phase and become infectable by HIV. And the way for HIV to do that providing two molecules, soluble CD23 and ICAM, to affect the expression of the cognate ligands on B cells. Three or four of those ligands on B cells determined whether we got a resting T cell that fits into G1 and gets infectable.

"I'll be looking for viral proteins to form the targets for new HIV drugs," Swingler said. "We've already got the ones that get rid of the viral load to the very lowest blood level. But HAART therapy isn't going to stop death from HIV," he concluded, "unless we can target this new latency reservoir."