Interleukin-2 (IL-2; Proleukin) causes long-lasting increases in CD4 cell counts by stimulating the cells to divide and then to survive for long periods, according to a small study presented in the on-line edition of The Journal of Clinical Investigation.
Giving repeated cycles of IL-2 to HIV-infected patients is known to cause dramatic increases in CD4 cell counts, which can last for up to ten years. However, researchers have been unsure how this is brought about in the body. It could happen due to an increase in the proliferation of new CD4 T-cells, an increase in their survival time, or a combination of both.
Investigators from the United States used cell-labelling techniques to discover that IL-2 caused an increase in proliferation of both CD4 and CD8 T-cells. However, it caused a dramatic increase in the life span of the new CD4 T-cells, but not the CD8 T-cells, accounting for the prolonged increases in CD4 cell counts.
“During IL-2 administration there is a dramatic increase in the proliferation of both CD4 and CD8 cells, with a peak proliferation of CD4 cells that is significantly greater than that of CD8 cells,” they write. “Second, the CD4 cells that proliferate during IL-2 administration have a profoundly prolonged survival.”
“The most critical effect in determining long-term CD4 cell increases in patients receiving intermittent IL-2 appears to be the increase in cell survival,” they explain.
The investigators gave the compound 2H-glucose to 35 volunteers, 27 of whom were HIV-positive and receiving antiretroviral therapy. Eighteen of the HIV-positive patients were also receiving cycles of IL-2 treatment.
Since 2H-glucose is converted into a compound that is taken up by cells that are dividing, the researchers could measure the rates of proliferation of the cells in each patient. This revealed that the HIV-positive patients receiving IL-2 had greater proliferation rates of CD4 T-cells (44%) than the HIV-positive patients not taking IL-2 (6%, p
Similar results were seen for CD8 T-cells (29% vs. 5% and 3% respectively; p
To examine the long-term effects of IL-2 administration, the investigators examined the decay in the labelled cells in two patients over a three-year period. They calculated that the numbers of CD4 T-cells would take 3.4 and 3.2 years to fall by 50% in these two patients. In contrast, the HIV-positive patients not taking IL-2 and the HIV-negative controls had median values of7 and 8 weeks, respectively.
The rate of decay of new CD4 T-cells was more rapid during the first two cycles of treatment than subsequent cycles. “This suggests that repeat cycles of IL-2 are necessary to prolong survival of CD4 cells,” explain the researchers.
In contrast, CD8 T-cells showed a smaller increase in survival, but this was similar during early and late cycles of IL-2 treatment.
“More CD4 and CD8 cells proliferated during IL-2 therapy, and, for the group as a whole, the CD4, but not the CD8, cells that proliferated survived longer in patients receiving multiple cycles of IL-2 therapy compared with controls,” the investigators write.
The researchers confirmed their results by using a different cell labelling compound, called bromodeoxyuridine (BrdU). This experiment also revealed that the survival of ‘naïve’ and ‘central memory’ CD4 T-cells was longer than that of the ‘effector memory’ cells.
“Central memory cells appear to be primarily responsible for surveillance and reinitiation of immune responses against pathogens previously controlled by the host,” write the investigators. “Since the majority of opportunistic infections seen in HIV-infected patients are caused by pathogens to which the host has previously been exposed, expansion of this pool of lymphocytes should potentially facilitate future control of these opportunistic infections.”
IL-2 is a licensed drug for treating a form of kidney cancer, but its use in people with HIV is unlicensed and experimental. If a doctor agrees to take full responsibility for its use, IL-2 can be prescribed to people with HIV outside of approved indications. IL-2 can also be accessed through clinical trials.
Kovacs JA et al. Induction of prolonged survival of CD4+ T lymphocytes by intermittent 1L-2 therapy in HIV-infected patients. J Clin Invest (on-line edition), 2005.