From Homer's Trojan Horse to the allies' misleading Hitler as towhere D-day forces would land, armies have deployedmisinformation to conquer their enemies. So far, the shifty humanimmunodeficiency virus (HIV) is winning its war, by means oftrickery, deceit and downright disinformation.
Now molecular geneticists and immunologists at Stanford Universityannounce a step toward blowing HIV's deepest cover and reddestherring. In this month's issue of The Journal of Clinical Investigation(JCI), they propose that the conventional measurement of dwindlingT lymphocytes in HIV-infected individuals misses the main point incombating AIDS. Their paper is titled, "CD8 naive T cell countsdecrease progressively in HIV-infected adults." (A companion articlein the same JCI reports similar findings in HIV-infected children.)
The paper's lead author, immunologist Mario Roederer, toldBioWorld Today that theirs' is "the first demonstration that HIVdisease involves the loss of both CD4 and CD8 cells."
He made the point that the decade-old practice of counting totallevels of CD4 helper, and CD8 killer, T cells is misleading, becauseit ignores the relatively neglected, and depleted, "naive" T cells asthe truest measure of AIDS, and clue to therapeutic countermeasures.
T lymphocytes start life in the bone marrow as uncommittedprecursor cells. These migrate quickly into the thymus for boot-camptraining in how to recognize foreign antigenic molecules Some learnto become CD4 helpers; others, CD8 killers.
Cutting Down Naive Cells In Their Prime
Once instructed, the thymus releases these T cells into thebloodstream, to lie in wait for the invaders they have learned totarget. There, they stay poised to go into action, and multiply intobattalions of single-purpose memory cells. But the insidious AIDSvirus doesn't wait for this to happen; it attacks and decimates thestill-unbloodied virgin cells before they have a chance to meet theirfirst alien antigen, and while their infection is still asymptomatic.
"People develop memory T cell responses that protect them frommany diseases," said Roederer. "HIV-infected people lose theseresponses. And without sufficient naive cells, they can't generate newresponses to overcome previously encountered infections."
The rise in CD8 killer T cells as infection progresses, he suggested, isdeceptive, as these are mainly memory cells programmed againstHIV antigens that may have already mutated. This spaying ofmemory cells prevents them from taking on the ever-changingmutations of the HIV-1 itself, each presenting a new antigenic profileto a largely unavailable cellular immune defense.
Half of all CD8 T cells in a healthy adult are naive, Roederer and hisco-authors found, but their ratio is less than 10 percent in those withadvanced AIDS. Parallel losses deplete CD4 naive cells too, and alsocorrelate with AIDS progression.
"Total CD4 counts don't reflect the ability of the immune system torespond to new infections," Roederer said. "But naive CD4 and CD8counts do. Both T-cell types could provide a more useful prognosticmarker."
This finding, he suggested, might explain why the immune systems ofHIV-infected people can't keep up with the ever-mutating virus, andwhy they fall prey to opportunistic infections. It might also explainwhy some with low CD4 counts survive a long time, and others, highon CD4, succumb early.
Current Approaches Court Failure
Leonard Herzenberg, the paper's senior author, puts into questionseveral AIDS treatment approaches currently under development."Many AIDS strategies being developed today," he said, "includingtherapeutic vaccines and some forms of gene therapy, would requirethe activity of naive T cells." But, he added, "Such approaches arealmost doomed to failure, in patients whose naive cell counts areactually quite low."
Roederer said that this Stanford study "forces us to reevaluate all ofthe experiments that have been done in the past 10 to 12 years on Tcell function with cells from HIV patients."
In the blood of over 250 HIV-infected individuals, he and hiscolleagues separated the naive T cell sheep from the committed CD4and CD8 goats by flow cytometry, a cell-sorting and -countingmethod invented by Leonard and Leonore Herzenberg in the 1970s.
"However," said Leonore, "now that we've done this basic study,people can use standard instrumentation to make the samemeasurements."
Roederer plans next "to get our hands on frozen-tissue data banksthat various clinical trials have saved in retrospective studies that goback three, five or 10 years. We would thaw them, and do themeasurements that we do to establish whether or not the change overtime for an individual patient is clinically relevant."
He recommended that "in future clinical trials of AIDS vaccines orimmunomodulatory therapy, investigators determine the number ofnaive cells that their patients have, because it's possible that theresponsiveness of a patient may depend on his or her naive cell count,rather than the CD4 count." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.