Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients
Joseph A. Kovacs, … , Dimiter S. Dimitrov, H. Clifford Lane
Joseph A. Kovacs, … , Dimiter S. Dimitrov, H. Clifford Lane
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2139-2148. https://doi.org/10.1172/JCI23196.
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Research Article AIDS/HIV

Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients

Abstract

HIV infection leads to decreases in the number of CD4+ T lymphocytes and an increased risk for opportunistic infections and neoplasms. The administration of intermittent cycles of IL-2 to HIV-infected patients can lead to profound increases (often greater than 100%) in CD4 cell number and percentage. Using in vivo labeling with 2H-glucose and BrdU, we have been able to demonstrate that, although therapy with IL-2 leads to high levels of proliferation of CD4 as well as CD8 lymphocytes, it is a remarkable preferential increase in survival of CD4 cells (with half-lives that can exceed 3 years) that is critical to the sustained expansion of these cells. This increased survival was time-dependent: the median half-life, as determined by semiempirical modeling, of labeled CD4 cells in 6 patients increased from 1.7 weeks following an early IL-2 cycle to 28.7 weeks following a later cycle, while CD8 cells showed no change in the median half-life. Examination of lymphocyte subsets demonstrated that phenotypically naive (CD27+CD45RO–) as well as central memory (CD27+CD45RO+) CD4 cells were preferentially expanded, suggesting that IL-2 can help maintain cells important for host defense against new antigens as well as for long-term memory to opportunistic pathogens.

Authors

Joseph A. Kovacs, Richard A. Lempicki, Igor A. Sidorov, Joseph W. Adelsberger, Irini Sereti, William Sachau, Grace Kelly, Julia A. Metcalf, Richard T. Davey Jr., Judith Falloon, Michael A. Polis, Jorge Tavel, Randy Stevens, Laurie Lambert, Douglas A. Hosack, Marjorie Bosche, Haleem J. Issaq, Stephen D. Fox, Susan Leitman, Michael W. Baseler, Henry Masur, Michele Di Mascio, Dimiter S. Dimitrov, H. Clifford Lane

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Figure 4

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BrdU labeling kinetics in 4 patients receiving a BrdU infusion immediate...
BrdU labeling kinetics in 4 patients receiving a BrdU infusion immediately after the last IL-2 dose. (A) Experimental data for CD4 cells, represented by blue squares, and for CD8 cells, represented by red triangles. For patient 3 (top panels), data following labeling before any IL-2 was received are shown by green squares (CD4) and black triangles (CD8). The solid lines represent the fitting by the model equations. (B) The probability density function of the normal distribution of log d multiplied by the total source of labeled cells (S) for the same patients. The last 2 patients were long-term responders (patients 1 and 19 from Figure 1). Mean log decay md values for these data are (CD4/CD8): pt. 3, 0.10/–0.07 (for labeling with no IL-2), 0.14/0.88 (cycle 1); pt. 8, 1.38/0.85; pt. 1, –1.34/0.11; pt. 19, –1.28/0.35. Consistent with the deuterium-labeling studies, the 2 long-term responders had a smaller md for labeled CD4 but not CD8 cells, indicating longer survival of the proliferating cells. (C) BrdU labeling kinetics in naive (CD27+CD45RO–), central memory (CD27+CD45RO+), and effector memory (CD27–CD45RO+ and CD27–CD45RO–) CD4 (top) and CD8 (bottom) subpopulations for patient 19. Presentation of data is as in A and B. For both CD4 and CD8 cells, md is substantially smaller (indicating a slower decay) for the 2 CD27+ populations. Mean log decay md values for these data are (CD45RO–/CD45RO+): CD4/CD27+, –1.58/–1.10; CD8/CD27+, –1.02/–1.32; CD4/CD27–, 0.69/2.32; CD8/CD27–, 0.07/1.92.