Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial

Lévy, Yves; Capitant, Catherine; Houhou, Sami; Carrière, Isabelle; Viard, JP; Goujard, Cécile; Gastaut, J. A.; Oksenhendler, Éric; Boumsell, Laurence; Gomard, E; Rabian, Claire; Weiss, Laurence; Guillet, J G; Delfraissy, J. F.; Aboulker, J. P.; Séligmann, M

doi:10.1016/s0140-6736(98)07345-0

Cited by 134 publications

(76 citation statements)

References 22 publications

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“…1,13,14 The same observation was made in this study. In the IL-2 group the median percent of CD4 ϩ T cells expressing CD25 increased from 19.6% to 53% and the CD4 ϩ /CD25 ϩ T-cell count increased from 89 cells/L to 360 cells/L (P Ͻ .001).…”

Section: The Expansion Of Cd4 ؉ /Cd25 ؉ T Cells After Il-2 Administrasupporting

confidence: 84%

IL-2–induced CD4+ T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation

Sereti

Anthony

Martinez-Wilson

et al. 2004

Blood

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Section: The Expansion Of Cd4 ؉ /Cd25 ؉ T Cells After Il-2 Administrasupporting

confidence: 84%

IL-2–induced CD4+ T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation

Sereti

Anthony

Martinez-Wilson

et al. 2004

Blood

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“…Multiple randomized trials have demonstrated that the administration of intermittent cycles of IL-2 to HIV-infected patients can lead to profound, sustained increases (often greater than 100%) in CD4 cell number and percentage (1)(2)(3). After 3 to 6 five-day cycles of IL-2 administered every 2 months, CD4 cell numbers may remain elevated for years without additional cycles.…”

Section: Introductionmentioning

confidence: 99%

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

Kovacs¹,

Lempicki²,

Sidorov³

et al. 2005

J. Clin. Invest.

114

101

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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 2 H-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.

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“…In the past 20 years, a large set of clinical trials demonstrated that intermittent interleukin (IL)-2 therapy increased the CD4 T cell pool in HIV-infected patients and induced, in a large majority of patients, significant and sustained increases in CD4 T cell count beyond that seen in patients treated with antiviral drugs alone. In particular, recombinant IL-2 therapy raised naive and central memory CD4 + cells expressing CD25, the α-chain of the IL-2 receptor, more than antiretroviral drugs alone (1)(2)(3)(4)(5)(6). This population accounted for up to 70% of the total CD4 + T cell pool of IL-2-treated patients and persisted for a long time.…”

mentioning

confidence: 99%

In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients

Weiss

Letimier

Carrière

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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HIV-1 infection is characterized by a progressive decline in CD4 + T cells leading to a state of profound immunodeficiency. IL-2 therapy has been shown to improve CD4 + counts beyond that observed with antiretroviral therapy. Recent phase III trials revealed that despite a sustained increase in CD4 + counts, IL-2-treated patients did not experience a better clinical outcome [Abrams D, et al. (2009) N Engl J Med 361(16):1548-1559. To explain these disappointing results, we have studied phenotypic, functional, and molecular characteristics of CD4 + T cell populations in IL-2-treated patients. We found that the principal effect of long-term IL-2 therapy was the expansion of two distinct CD4 + CD25 + T cell populations (CD4 + CD25 lo CD127 lo FOXP3 + and CD4 + CD25 hi CD127 lo FOXP3 hi ) that shared phenotypic markers of Treg but could be distinguished by the levels of CD25 and FOXP3 expression. IL-2-expanded CD4 + CD25 + T cells suppressed proliferation of effector cells in vitro and had gene expression profiles similar to those of natural regulatory CD4 + CD25 hi FOXP3 + T cells (Treg) from healthy donors, an immunosuppressive T cell subset critically important for the maintenance of self-tolerance. We propose that the sustained increase of the peripheral Treg pool in IL-2-treated HIV patients may account for the unexpected clinical observation that patients with the greatest expansion of CD4 + T cells had a higher relative risk of clinical progression to AIDS. molecular profiling | immune-based therapy H IV infection is mainly associated with a progressive decrease in the number of CD4 + T lymphocytes and defective CD4-and CD8-specific T cell responses against HIV and other pathogens. Quantitative and qualitative CD4 T cell reconstitution following introduction of antiretroviral therapy (ART) in HIVinfected patients is often incomplete, leading one to evaluate the impact of immune-based therapy in combination with ART. In the past 20 years, a large set of clinical trials demonstrated that intermittent interleukin (IL)-2 therapy increased the CD4 T cell pool in HIV-infected patients and induced, in a large majority of patients, significant and sustained increases in CD4 T cell count beyond that seen in patients treated with antiviral drugs alone. In particular, recombinant IL-2 therapy raised naive and central memory CD4 + cells expressing CD25, the α-chain of the IL-2 receptor, more than antiretroviral drugs alone (1-6). This population accounted for up to 70% of the total CD4 + T cell pool of IL-2-treated patients and persisted for a long time.The clinical impact of IL-2 was evaluated in two long-run large phase III trials (SILCAAT and ESPRIT) involving almost 6,000 chronically HIV-1-infected patients. Results recently reported showed that, despite a sustained increase in CD4 + T cell counts, over a median follow-up of 7-8 years, IL-2-treated patients did not experience a better clinical outcome (7). These disappointing results have remained unexplained so far.In mice, IL-2 has been shown to be essential for the...

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Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial

Cited by 134 publications

References 22 publications

IL-2–induced CD4+ T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation

IL-2–induced CD4+ T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation

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

In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients

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Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial

Cited by 134 publications

References 22 publications

IL-2–induced CD4+ T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation

IL-2–induced CD4+ T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation

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

In vivo expansion of naive and activated CD4 + CD25 + FOXP3 + regulatory T cell populations in interleukin-2–treated HIV patients

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In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients