The Body Covers: The 1st International AIDS Society Conference on HIV Pathogenesis and Treatment
Therapies Directly Targeting the Immune System
July 10, 2001
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It is well known that one of the primary advantages to the intermittent administration of interleukin-2 (IL-2) to HIV-infected patients is a sustained expansion of their CD4+ T cells. This expansion does not occur, however, in the CD8+ T cell pool, despite substantial increases in proliferation in CD8+ T cells during an IL-2 cycle. Researchers at the National Institutes of Health designed this study, which was presented at an oral plenary session at the 1st IAS Conference on HIV Pathogenesis and Treatment, to better understand the mechanism by which IL-2 causes CD4+ T cell expansion and the long-term effects of IL-2 on T cell proliferation.
Frozen peripheral blood mononuclear cells (PBMCs) from eighteen patients participating in a randomized-controlled trial of IL-2 therapy were collected at baseline and at twelve months of therapy. Nine patients were treated with antiretroviral therapy, which was limited to nucleoside analogues at the time the study was performed, and with five-day cycles of intravenous IL-2 every eight weeks. Nine control patients received antiretroviral therapy alone, again with only nucleoside analogues. CD4+ and CD8+ T cells from these two groups of patients were examined for expression of the Ki67 nuclear antigen, a marker of proliferation, CD25, and CD45RO and CD27, markers of memory and naive T cells, respectively.
During the twelve months of the study, the CD4+ T cell counts increased in IL-2 recipients from 442 to 1160 cells/mm3 , while in patients just on antiretrovirals that count decreased from 495 to 439 cells/mm3. A significant decrease in the percent of CD4+ T cells expressing Ki67 was observed in IL-2 treated patients, with a mean Ki67 level of 10.7% at baseline and 5.9% at month 12 (p=0.0002). This decrease did not occur in the control patients. Further, the decrease in Ki67 was found in both naive and memory CD4+ subsets, as well as in the CD25+ fraction of the CD4+ T cells. On the other hand, expression of Ki67 by CD8+ T cells did not change significantly from baseline in either group.
This study indicates that the selective expansion of the CD4+ T cell pool induced by intermittent IL-2 is associated with a long-term decrease in CD4+ T cell proliferation, as measured by Ki67 expression, and suggests that the enhanced survival of CD4+ T cells is important in maintaining this expansion.
Thus IL-2 is effective in increasing the survival of CD4+ T cells and in decreasing CD4+ T cell turnover, which -- in the highly activated state induced by HIV -- is one of the primary ways CD4+ T cells are lost. This finding may have implications regarding IL-2 treatment issues and potentially may allow for some simplification of that therapy, which is one of the major impediments to its widespread use.
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