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Dutch Research Team Challenges Ho/Shaw Pathogenetic HIV Model and Gives Cause for Pause

Telomeres' fifteeen minutes

As long ago as 1995, when the back-to-back Ho and Shaw viral dynamics papers were published, HIV disease has been likened to a colossal bathtub-or sink rather. The thinking went like this: the pool of CD4+ T lymphocytes ("CD4 cells") coursing through your body can be thought of as a sink of water. And like most sinks, this sink has both a faucet (or "tap") and a drain. Open the tap, and the level of water in the sink begins to rise; open the drain, and water rushes out. Pretty basic, TAG's Gregg Gonsalves explains.

Dr. Ho began using this analogy for what happens to the body's population of CD4 cells throughout the course of HIV infection. According to the now nearly universally accepted "sink" model, a normally functioning immune system consists of a tap from which constantly flows a moderate volume of new T-cells (to replace old ones as they naturally die, self-destruct or senesce) and a drain through which trickles only a small number of old and non-functional T cells. In HIV disease, however, the drain is wide open, and CD4 cells, as a result of direct killing of cells by the virus, immune system killing of virus infected cells, cell suicide or, most likely, a combination of these (and quite possible other) events, are being sucked out the drain like street soiled rainwater down a storm sewer during a midsummer downpour. Even were the body's immune system to try to compensate (which it appears to) for the accelerated loss of CD4 cells by opening the tap to full throttle, it still could not quite keep up with the action down there at the drain-and the level of "water" (the body's CD4 cell count) gradually falls until the sink holds but a shallow puddle. "Plug up the drain," the sink proponents argue, and you'll stem the progressive immune deficiency. As a result, the vast majority of therapeutic approaches to HIV infection have focused on "plugging up the drain," that is, halting the destruction of CD4 cells by stopping the virus.

November 1996: The Third International Congress on Drug Therapy for HIV Infection was held in Birmingham, England. A team of hotshot young virologists from the University of Amsterdam and the Amsterdam Medical Center (among them Frank Miedema, Jaap Goudsmit, Jaap Lange, Sven Danner) presented data suggesting that this "sink" model of HIV infection is all wrong. Rather than AIDS being caused by exhaustion of the regeneration capacity of the immune system as a result of high T cell turnover (the "drain"), the researchers claimed, AIDS is caused instead by interference with T cell renewal (the "tap"). At the very foundation of their blasphemous assertion was work done with hitherto obscure bits of protein call "telomeres."

Telomeres are lengthy stretches of contiguous, repeated simple DNA sequences (in vertebrates: TTAGGG x n) at the very end of chromosomes which play an important role in maintaining chromosomal integrity. When a cell divides, one end of the cell's chromosomes never gets fully replicated; the enzymes responsible for copying the chromosomes for the new cell always stop just short of the end of the line. So telomeres serve as a sort of genetic padding at these ends-padding that can be left behind without detriment to the cell as it divides. This ensures that no important genetic information is lost in the transfer to the next generation of cells.

In humans, telomeres are initially 10 kilobases in length. After about 25 cell divisions (which generally takes decades in a normally functioning human body, at a loss of 30-50 base pairs per year for normal human cells), cells can no longer divide and enter into an irreversible state of growth arrest known as "replicative senescence." By this point, telomere lengths have shortened to a mere 5-7 kilobases. Although somewhat esoteric, this phenomenon comes in quite handy: by looking at the shortening of telomere lengths over time one can assess both the replicative history and the proliferative potential of the cells in question.

With this as a backdrop, one of the obvious questions in the search to understand how HIV infection leads to immune system collapse in humans is whether or not the high rate of CD4+ cell turnover first reported by David Ho and George Shaw's laboratories is also accompanied by telomere shortening. It is exactly this question which Miedema and his Dutch colleagues presume to have answered. First presented at the Birmingham meeting, and then published shortly thereafter in the November 29 issue of Science magazine, the Dutch team concluded that, "Our data do not support the idea of high rates of production and destruction of CD4+ T cells as depicted in the 'sink model' proposed by Ho et al." Rather, "we suggest that HIV-1 infection is slowing down the flow of the tap, that is, the generation of new cells from an as yet undefined precursor source." Of interest, however, is the fact that Miedema did find shortened telomere lengths in CD8+ cells from HIV-infected individuals. This confirms a recent study by Janis Giorgi of UCLA, who reported last July that the CD8 telomere length in HIV-positive persons approximates that of healthy centenarians (AIDS 1996;10:F17-22).

The Dutch investigators hypothesize that HIV infection may interfere with the generation of CD4+ T-cells "through (i) the infection of stromal cells or microenvironment damage or both; or (ii) by infection of dividing CD4+ cell precursors, which would therefore abort the influx of new cells." Stromal cells are large, spread out cells that provide a bed for many blood cells; in this case, developing T-cells in the thymus. Thymic stromal cells play an important role in T-cell maturation. Their infection or the destruction of the thymic microenvironment where they reside-and where T-cells develop-would have disastrous consequences for the generation of T-cells. Additionally, if T-cells, before they mature into CD4+ or CD8+ cells from CD4+CD8+ precursors, were infected and killed by HIV, there would also be a crisis in the influx of new T-lymphocytes.

Miedema and his collaborators realize that there is not a lot of experimental evidence for their hypothesis. In fact, their data suggesting that CD4+ cells are not turning over rapidly-but that CD8+ cells are-belies a hypothesis that depends on destruction of CD4+CD8+ precursor cells. Miedema et al. propose that the increase in CD4+ cell counts after treatment with potent antiretroviral regimens may not be due to repopulation with newly generated cells, but effected by redistribution ("retrafficking") of activated memory CD4+ cells instead. This mechanism of CD4+ repopulation is seen after ablative cancer chemotherapy; the only difference being that following cancer chemotherapy CD4+ cell replenishment requires a full 10 months or so-and all the newly generated CD4+ cells are CD45RA+, that is, of a naïve phenotype.

Needless to say, the Dutch paper has generated a great deal of controversy. Miedema's own admission of a lack of evidence to support their provocative conclusions is mirrored in the skepticism of other investigators about the interpretation the Amsterdam investigators have derived from their data. By comparison, the Ho-Shaw "sink" model has a great deal of data to back it up. Many groups have shown that there is a high level of activation in the T-cell compartment-and activated cells are very likely to be dividing.

Ho et al. have shown that there are billions of cells at any given time expressing cell surface proteins associated with cell proliferation (ki67). Miedema's own group has shown that there are a large number of cells dying as a result of programmed cell death (apoptosis). To maintain stable CD4+ cell numbers over the short term (as is generally seen in the intermediate years of HIV infection), rudimentary mathematics dictate that there must also be a comparable influx of new cells. Miedema and his colleagues fail to address this apparent contradiction.

As for the ADARC group's response to the Miedema challenge, Diamond's Bill Paxton notes that the heretical proposition of Miedema et al. is but one possible explanation for what's going on. "At the end of the day," Paxton advises, that paper is open to interpretation." New studies which radioactively tag cells from SIV-infected and uninfected monkeys may help to resolve this important debate.