Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients
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
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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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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Deuterium incorporation by CD4 and CD8 cells. (A) Mean peak deuterium in...
Deuterium incorporation by CD4 and CD8 cells. (A) Mean peak deuterium incorporation was significantly higher in HIV-infected patients receiving IL-2 (n = 18) for both CD4 and CD8 cell populations when compared with HIV-uninfected controls (n = 8) and HIV-infected patients who did not receive IL-2 (n = 9) (P < 0.001 for all comparisons, Student’s t test). Error bars represent the standard deviation. (B and C) Deuterium labeling kinetics in 2 HIV-infected patients who did not receive IL-2 (patients 20 and 22, Table 1) and an HIV– volunteer (patient 30) (B) and in 3 HIV-infected patients who were long-term participants in intermittent IL-2 studies (patients 1, 2, and 4) (C). Patients 1 and 2 were long-term responders (see Figure 1 and Table 1), while patient 4 did not exhibit a CD4 count increase during IL-2 therapy. The continuous lines represent the fitting of the experimental data points (individual symbols) by the model equations. For the first 2 patients, the open symbol represents the percentage deuterium incorporation in cells obtained from a lymph node biopsy (at approximately 3 months). Time 0 is the beginning of the 2H-glucose infusion, which started 2 days after initiation of IL-2 treatment. (D) The probability density function (PD) of the normal distribution of log d multiplied by the total source of labeled cells (S) for the patients in C. The mean log decay rate constants (md) for CD4/CD8 cells for the patients are, respectively: patient (pt.) 1, –2.68/–1.68; pt. 2, –2.44/–1.44; pt. 4, 1.16/0.52. One log difference represents a 10-fold difference in half-life.