Tortoise Tale: Ten Years On, Feckless IL-2 Researchers Plod Ahead, Certain Of Success
HIV disease is characterized by the progressive depletion of CD4+ T-cells, and the cytokine IL-2 (a.k.a. "T-cell gowth factor") is the hormone-like peptide that allows one T-cell to turn into a hundreds. IL-2 also boosts the antiviral activity of natural killer (NK) cells, which are thought to play a crucial role in the control of HIV in vivo.
Over the past decade, it has been proposed that HIV-related T-cell depletion and disease progression are caused by the dysregulation and underproduction of IL-2 by immune cells. T-cells from HIV-infected persons do not express sufficient amounts of IL-2 and, in the absence of IL-2, cannot divide and function properly in response to antigenic stimulation. A lack of IL-2 can cause T-cells to become unresponsive ("anergic") to pathogens that they should be fighting against. Moreover, it is thought that an IL-2 deficiency is involved in the induction of a form of cell suicide, called "apoptosis" or "programmed cell death." In this phenomenon, cells that are stimulated to divide, but can't because of an absence of IL-2, become "programmed" to die. IL-2 has been in AIDS clinical trials for over ten years now, and yet no conclusive evidence regarding its potential benefit to people with HIV infection has been forthcoming. This is due, in part, to the fact that IL-2 is an HIV-inductive cytokine; that is, that the addition
of IL-2 to any system containing HIV-infected T-cells causes the production of more HIV as T-cells undergo cell division. More T-cells, more HIV.
IL-2's activity on T-cells also leads to the expression of what are called "secondary" cytokines, one of which, TNF-alpha, can also rev up production of new HIV. Because the goal of high-dose IL-2 therapy is to stimulate the growth of T-cells (which, in turn, leads to increased retroviral production), IL-2 trials have needed to include the use of an antiretroviral, mostly AZT. Unfortunately, most trials of combination IL-2+AZT did not account for AZT's blink-of-the-eye antiretroviral activity, and so at least some patients were functionally not receiving any antiretroviral "cover" from the combination. Any possible benefits of the IL-2+AZT combination were thus rendered undiscernible. Future studies are being planned for people who have little or no prior AZT use and with combination antiretroviral "cover", including the Merck protease inhibitor.
The concern that the quantity of IL-2 needed to induce massive T-cell growth would also induce massive HIV replication has caused some investigators to employ smaller dosages of IL-2 towards more modest ends: boosting the activity of NK cells. Since NK cells express high levels of IL-2 receptors on their surface, smaller amounts of IL-2 are needed to exert their effects on these cells than on T-cells. Smaller dosages of IL-2, the theory goes, could boost NK cells while exerting only a mild stimulatory effect on T-cells. Therefore, the goals of lower- and low-dose IL-2 trials have been to 1) increase NK function and 2) improve T-cell function and IL-2 sensitivity without necessarily increasing T-cell numbers.
High-dose IL-2, however, continues to be tested - both in the laboratory and in the clinic. And in the context of immune restoration, IL-2 remains one of the leading candidates for so-called "immuned-based therapy" (IBT). But despite its in vitro effects on T-cells, a number of hurdles (HIV activation notwithstanding) have presented themselves in the attempts by investigators to apply IL-2 in vivo towards the quantitative and qualitative reconstitution of normal immune function. The first to be noticed was the severity of dose-limiting toxicities: the dosage required to substantially boost CD4+ T-cell numbers tends to engender a host of ugly side-effects - from flu-like symptoms to pneumonia to vascular leak syndrome (very dangerous!).
Secondly, because of the very short half-life of the molecule, IL-2 must be infused over long periods of time to produce significant CD4+ T-cell increases. These increases, though, quickly disappear in spite of continued infusions. This, it turns out, results from the over-expression of IL-2 receptors (IL-2r), which detach themselves from cell membranes and neutralize IL-2 in the serum, rendering further IL-2 administration useless.
NIH's Joseph Kovacs and Clifford Lane have been working through some of these hurdles. They reported results from a small trial utilizing "intermittant continuous" infusion of high doses of IL-2. According to their reports, this method of administration side-steps the mechanism that led to the over-expression of IL-2r. They have been able to generate sustained CD4+ T-cell increases of greater than 50 per cent by giving patients five day infusions every eight weeks. These dramatic results, however, occurred in 6 of the 10 patients who had greater than 200 CD4+ T-cells/mm3 at study entry. Only 2 of the 12 patients with fewer than 200 CD4+ T-cells/mm3 at baseline showed any T-cell rises from this regimen. And no patients with fewer than 100 CD4+ T-cells showed any signs of improved immunologic function.
This latest NIH trial has answered several questions about treatment with high-dose IL-2 in combination with an antiretroviral therapy. First of all, it has designated what appears to be an acceptable dose - and dose-reduction scheme -in terms of benefits vs. toxicities. Secondly, it demonstrated an interesting pattern in outcomes which is likely to influence the design of future IL-2 trials: virtually all patients, regardless of baseline CD4+ T-cell count and prior antiretroviral use, experienced "spiking" increases in both CD4+ T-cell number and HIV RNA levels immediately following IL-2 infusion. In certain patients (CD4>200), the CD4+ T-cell increases were sustained, while HIV RNA levels returned to baseline. In most of the remaining patients the opposite occurred: HIV RNA increases were sustained while CD4+ counts returned to baseline or below baseline. This implies that a tenuous balance exists between the ability of IL-2 to spur the growth of new CD4+ T-cells, and its deleterious effects mediated through
increased viral production.
The ACTG is about to implement a low-dose, subcutaneous IL-2+AZT protocol, chaired by Philadelphia's Dr. Heddy Teppler. And Clifford Lane's lab at NIH is following up its most recent trial with an identical trial in 60 patients with CD4 >200, as well as a high-dose subcutaneous trial that will use the same intermittant continuous dosing regimen. His lab is also planning a comparative trial of high-dose IL-2 given continuously for three, four or five days every eight weeks.