Pulling the Plug on T-Cells
Fascinating Work on HIV and T-Cell Kinetics Challenges Longtime Dismissal of Ravaged Immune System's Regenerative Potential
The CTL As Both Villain and Victor
Picture this. Dr. David Ho approaches a half-filled tub of water, with water still more or less pouring in from an open spigot. "This is your immune system." He removes his watch, rolls up his shirt sleeve, swirls his immersed hand around in the frigid water and looks out to his awestruck proteges. "These are your T-cells." He then savagely yanks out the drain's stopper and holds it up demonstrably for an awestruck audience to see. "This ... is what HIV does to your T cells." Water begins rushing out of the tub, the water level noticeably falling, partly, but not all the way. (Since the spigot is still wide open, the tub does not immediately become completely empty.) "Want a tub to remain full of water?" he surveys his audience with a smug air of over-simplification. "Would you, A, open the spigot to full throttle? Or, B, simply plug the drain? Why, you'd plug the drain, of course. I rest my case."
"It's the virus, stupid" has been the mantra of U.S. virologists ever since the first immune-based approaches to HIV were ever posited. "Once you're down around 500 T-cells," erstwhile ACTG Executive Committee honcho Larry Corey once opined, "the immune system is so completely obliterated there's not a chance in hell of reconstitution."
"HIV, stupid." "There's lots of it around," so the model goes, "more than first imagined" (Pantaleo, G et al. Nature 362. 355-358, 1993; and Embretson, J et al. Nature 362. 359-362, 1993). "And it's directly," solely, they'd argue, "responsible for the T-cell killing that's going on throughout the body" (Ho, D et al. Nature 373. 123-126, 1995; and Wei, X et al. Nature 373. 117-122. 1995). "Stop the virus, and you stop AIDS."
With this as a backdrop, it is useful to approach the two recent Nature papers, and all associated press accounts which spin off of them, from within the minds of their authors: extremely bright, ambitious virologists determined to prove their common hypothesis. The two principal questions for people with HIV and their advocates are: 1) How well does this new research advance our knowledge of HIV pathogenesis? and 2) What, if any, are the clinical implications of this research?
It's easiest to begin with what the research does not address: namely, 1) By what mechanism(s) HIV is cleared from the body; 2) How CD4+ T-cells are ultimately destroyed; 3) How these elegant viral kinetics in mostly symptomatic patients translate to earlier stages of disease; and 4) How viral kinetics may differ in other immune system compartments, i.e., lymphoid tissue, macrophages, brain and gut.
At the same time, however, the papers offer some extraordinary insight into the regenerative capacity of the human immune system (the total volume of CD4+ T-cells is restored approximately every 15 days, and people with the lowest T- cell counts showed the highest T-cell rises in response to antiretroviral therapy) and throws somewhat of a monkey wrench into previously conceived notions of the relationship between disease stage and viral dynamics (rate of viral clearance was virtually the same across all disease stages, and no correlation was found between CD4+ T-cell count and level of plasma viremia, see cover page graphic).
Finally, with such an enormous volume of CD4+ T-cells being destroyed and replenished each day (somewhere around the order of 10 billion cells daily), the significance of apoptosis, or programmed cell death, may be somewhat diminished as a possible explanation for CD4+ T-cell depletion. As Dr. Ho puts it, "The apoptosis commonly observed in the setting of HIV-1 infection may simply be an expected consequence of an active lymphocyte regenerative process."
So far, so good. There's a lot more virus, and viral replication, around than we may have thought even one year ago subsequent to the publication of the Fauci/Pantaleo paper. And that virus (though not explicitly stated in either of the two Nature papers, but detailed in other fora by highly esteemed researchers, among them erstwhile Harvard virologist William Haseltine and Pasteur's Simon Wain-Hobson) is generously sown throughout the lymph tissues within the first couple of weeks of infection, comprising some 1M genetically distinct viral variants (more like 100M to 1B viral variants in late stage illness). Is it any wonder, then, that drug-resistant virus emerges within 14 days' time after antiviral therapy given this clever genetic diversification strategy and the newly revealed viral kinetics?
With all this virus around (once someone has proven that it's the virus that's directly killing the T cells and destroying the architecture of the lymph nodes), one might aruge, as both Ho and Shaw do, that "treatment strategies must be initiated as early in the course of infection as possible, perhaps even during seroconversion." Dr. Shaw would go even further, arguing that his work makes quite a strong case for early-as-possible intervention with combination therapy.*
The devil though, as always, is in the details. What treatments, Dr. Ho? What combination, Professor Shaw? With all these viral variants hanging around, with such a dastardly, as Dr. Ho so cogently put it in a recent interview, "acute infection that never goes away," one would indeed either need to initiate combination therapy concurrent with initial infection (and even that may not work: see Palmer DL et al., "HIV-1 Infection Despite Immediate Combination Antiviral Therapy After Infusion of Contaminated White Cells, Am Jrnl Med 97: 289-94) or devise a resistance-proof combination of different classes of drugs that simply aren't, or near to becoming, on hand at the moment! In an interview with New York Newsday's ace science reporter Laurie Garrett, Dr. Ho was asked for specifics about his "as early in the course of infection" recommendation. "With the drugs we have today, Dr. Ho?" she pressed, "Or 'the' drug?" Ho replied demurely, "Well, with 'the' drug."
Now picture this. A gradually emptying tub of water. Water rushing in; water rushing out. There's no plug for the drain. But while you're searching for one, there's a good chance you could raise the water level, and perhaps even keep it at a reasonable level, by opening that spigot to full throttle, increasing the in-flow of water. What do you do? †
*Others (Concorde principal investigators Ian Weller and M. Seligman come to mind) would argue that what the Nature papers most elegantly demonstrate is the immense and long-term effectiveness of the body's own immune response to HIV infection and thus advocate for saving the limited antiretroviral "bang" of currently available therapies for when the body most needs the help: much later in the disease.