Just as Michigan's "Doctor Death" helps life-sick individualscommit suicide, so the AIDS virus -- besides killing infected Tcells -- prompts uninfected ones to kill themselves.

Such, at least, is a scenario advanced by the Pasteur Institute'sLuc Montagnier, co-discoverer (some say, first discoverer) ofHIV, the human immunodeficiency virus.

Montagnier proposes his theory of programmed cell death as akey factor in HIV's onslaught on the immune system in today'sScience. His brief "Perspective" is titled simply "Apoptosis inAIDS," which says it all.

Apoptosis means programmed cell death, the suicidal oppositeof necrosis, which disintegrates cells. Every day, a significantproportion of the cells in the human body die and are replacednaturally by spontaneous activation of the pathway leading toapotosis, said Stuart Schlossman, chief of tumor immunology atDana-Farber Cancer Institute, and a discoverer of the helper Tcell's CD4 membrane glycoprotein.

Self-slaying cells go gentle into the good night of apoptosis,which Schlossman calls "a calm and orderly process that endsin DNA fragmentation and cell death." Necrosis, by comparison,is an acute, lethal consequence of stress. A cell undergoingapoptosis simply condenses its nuclear DNA, which getsabsorbed.

During development, the thymus eliminates 99 percent of itsburgeoning immune-cell population, to get rid of non-functioning and autoreactive cells, and so condition the body'simmune system to self-tolerance.

Montagnier points out that this normal process of programmedcell death, essential to T-cell maturation, can be rudelytriggered in immature T-cell precursor cells by radiation,calcium ion carriers, glucocorticoids, oxygen radicals, and othereffectors. Mature T cells are resistant to such suicidal agents,and respond by self-proliferation and cytokine secretion.

"Now, new findings suggest another potential mechanism," theFrench virologist announced. "In HIV-infected patients, the lossof CD4+ cells is associated with lymphocyte activation, but thisdoes not result in cell proliferation, as it does normally, butrather in @ programmed cell death."

"Loss of T cells is what kills you in AIDS," observed Schlossmanlaconically, "and that causes the immunodeficiency." Hesuggested that "what Montagnier is saying is that maybe ananti-viral isn't going to be the answer."

But like almost every other facet of AIDS research, there aremore unknowns than knowns. "It is not clear whether the AIDSvirus, in addition to infecting and killing T cells by moreconventional means, can actually induce apoptosis by causingactivation of these cells," Schlossman cautions. But he added,"It's certainly a mechanism that's as good as any other, if notbetter than most."

This form of T-cell suicide, Montagnier suggested, couldpotentially be suppressed by adding a second stimulus, such asinterleukins, which restore antigen-dependent T-cell activation.

As a "good candidate" for AIDS-related apoptosis, he fingersgp120, the HIV envelope protein, which binds CD4 receptors. Itthen preps normal CD4+ cells for death, in response tosubsequent T-cell receptor stimulation. This mechanismexplains how non-infected cells die off and devastate thepatient's immune defenses. The gp120 primes neighboringuninfected cells by cross-linking of CD4 molecules.

So far, all of Montagnier's findings and surmises derive from invitro or primate experiments. "The full relevance of theseobservations in vivo," he said, "remains to be determined."

One key question: Is there any evidence that binding of CD4receptors on lymphocytes by gp120 actually occurs in AIDSpatients? He pointed out that the site on the CD4 receptor thathooks up with gp120 is often masked in humans, presumablyby the envelope protein itself. Treatment with AZT rapidlyunmasks these critical docking grooves, but only transiently.

Montagnier sees such unmasking as a marker for clinicalevaluation of anti-viral drugs. He grants that soluble CD4 hasproven a let-down as a viral inhibitor, competing with gp120 tomount the receptor. But he proposes that it "could have abeneficial effect on the course of the disease by preventingabnormal signaling of the soluble CD4 lymphocytes due to thebinding of the viral protein."

The French scientist challenged the pharmaceutical industry to"re-enter this neglected field, and make sufficient amounts ofsoluble CD4 for clinical trials."

Recognizing the failure of anti-viral therapy, he proclaimedthat "the time has come to fight this complex disease bycombinations of several treatments, including anti-virals,antibiotics and anti-apoptotic drugs."

Industry is beginning to catch on. Patrick Kung, a foundingfather of T-cell science research and of T Cell Sciences Inc. ofCambridge, Mass., calls Montagnier's HIV-apoptosis rationale "avery powerful argument." Kung told BioWorld, "I feel that thevarious mechanisms cited in his article, operating in the testtube, are a very good basis for us now to search for therelevant apoptosis mechanisms operating in vivo."

Dana-Farber's Stuart Schlossman is the principal researcher ofApoptosis Technologies Inc. (ATI), a single-purpose spin-off ofImmunoGen Inc., also of Cambridge. He and his collaborator,Paul Anderson have discovered a protein, TIA-1, in cytotoxic Tcells, which potentially can prevent abnormal programmed celldeath in AIDS patients. Echoing Montagnier's appeal,Schlossman called on the pharmaceutical industry to "thinkabout this other mechanism. You may be able to interfere withthe natural death of these cells and extend the life-span ofAIDS victims by a very long period of time."

He buffers this challenge by emphasizing that ATI "is notloudly saying that HIV is their area of major interest. They'retrying to get the basic mechanisms worked out. But we believethese will be strongly applicable to AIDS."

Immunotoxicologist David Sherr told BioWorld that"ImmunoGen's ATI approach to apoptosis focuses on cancer, notAIDS.

"Their strategy," said Sherr, who teaches environmental healthat Boston University's School of Public Health, "is to inducedeath in tumor cells by putting a toxin onto an antibodytargeted at the tumor." He added that they have taken upSchlossman's TIA protein, which is "basically a high-tech toxin,and that tumor-targeting approach would have nothing that Iknow of to do with preventing cell death in AIDS."

Instead, Sherr picks up on one other cell suicide-stopping ploythat Montagnier cited: abating free oxygen radicals, whichcause DNA damage in cells. "One of the theories of programmedcell death," Sherr explained, "is that you have a lot of oxygenradicals around, damaging DNA, so the cell decides to commitsuicide rather than risk transformation to a tumor." In AIDS, hesurmises that "treating people with oxygen radical scavengers,such as N-acetyl-cystein, is not going to prevent the infection,but will put off cell death for a time.

"There's a huge market out there for apoptosis," Sherr declares."Besides AIDS, programmed cell death has been implicated inAlzheimer's, cancer and aging. You can't get much bigger thanthat."

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.