CD4 T Cell Survival after Intermittent Interleukin‐2 Therapy Is Predictive of an Increase in the CD4 T Cell Count of HIV‐Infected Patients

ABSTRACTEarly HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidantN-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection.IMPORTANCEThe persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.

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A case of multidrug resistant primary HIV infection with delayed CD4 T-cell count decline despite low viral load, treated with interleukin-2

AIDS ◽

10.1097/01.aids.0000237378.69433.6b ◽

2006 ◽

Vol 20 (11) ◽

pp. 1564-1565

Author(s):

David Pao ◽

Erasmus Smit ◽

Nesrina Imami ◽

Martin Fisher

Keyword(s):

Viral Load ◽

T Cell ◽

Hiv Infection ◽

Cell Count ◽

Interleukin 2 ◽

Multidrug Resistant ◽

Cd4 T Cell ◽

Primary Hiv Infection ◽

Cd4 T Cell Count

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Beta-2 Microglobulin and Soluble Interleukin-2 Receptor Serum Levels Correlates with Human Immunodeficiency Virus Associated Non-Hodgkins Lymphoma-Diffuse Large B-Cell Lymphoma (HIV-NHL-DLBCL).

Blood ◽

10.1182/blood.v106.11.4675.4675 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4675-4675

Author(s):

Eugene McPherson ◽

J. Ng ◽

E. Hazel ◽

P. Tassy

Keyword(s):

Viral Load ◽

T Cell ◽

Cell Count ◽

Interleukin 2 ◽

Serum Levels ◽

Cd4 T Cell ◽

Soluble Interleukin 2 Receptor ◽

Beta 2 ◽

Beta 2 Microglobulin ◽

Cd4 T Cell Count

Abstract Beta-2-microglobulin (B2M) is a cell surface protein on many somatic cells including T and B lymphocytes and macrophages as a subunit of class I major histocompatibilty complex (MHC). Soluble interleukin-2 receptor (sIL-2R) is a T cell derived cytokine that induce proliferation of activated T cells, participates in differentiation of B cells and modulates macrophage function and phenotype. Both serum B2M and sIL-2R levels reflect immune-system activation and are elevated in patients with HIV-NHL-DLBCL. Combined detection of B2M and sIL-2R can be used to predict treatment response or failure in patients with aggressive HIV-NHL-DLBCL. When highly active antiretroviral therapy (HAART) chemotherapy is administered to refractoriness of elevated B2M and sIL-2R serum levels may be seen in HIV-NHL-DLBCL poor responders or failures. As sIL-2R levels decrease, B2M levels remain elevated in early stage HIV-NHL-DLBCL. Treatment of these patients with CHOP-rituximab and HAART both markers decrease. However, in late stage disease (stage III-IV, HIV-NHL-DLBCL based on DLBCL), B2M and sIL-2R remain significantly elevated and prognosis poor even after immune restoration of CD4+ T cell count and HIVRNA viral load approach normal. CASE: We present one of several cases - a 38 year old HIV positive male with DLBCL of his sinus turbinates, had turbinectomy surgery with sIL-2R level of 617 U/mL (5,460.226 pg/ml) postop which gradually increased to 27,673.95 pg/ml in less than six months. The B2M level while on HAART decreased from 18.8 mg/L to 4.4 mg/L. His LDH, CRP, and GGT levels were elevated but the CD4+ T cell count was 26% and his HIVRNA viral load became undetectable. After CHOP-rituximab therapy sIL-2R decreased to 10,806 pg/ml from 27,674 pg/ml but slowly rose to 39,975.25 pg/ml and B2M increased to 19 mg/L. The CD19+ B cell count was zero and a CD4/CD8 ratio improve to 0.546. CONCLUSION: B2M and sIL-2R serum level measurements provides data that when used together may offer a better management approach to these HIV-NHL-DLBCL patients. B2M and sIL-2R elevated refractory levels correlates with tumour burden and predicts poor prognosis in aggressive HIV-NHL-DLBCL.

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