Alteration of tumor necrosis factor-alpha T-cell homeostasis following potent antiretroviral therapy: contribution to the development of human immunodeficiency virus-associated lipodystrophy syndrome.
Highly-active antiretroviral therapy (HAART) has lead to a dramatic decrease in the morbidity of patients infected with the human immunodeficiency virus (HIV). However, metabolic side effects, including lipodystrophy-associated (LD-associated) dyslipidemia, have been reported in patients treated with antiretroviral therapy. This study was designed to determine whether successful HAART was responsible for a dysregulation in the homeostasis of tumor necrosis factor-alpha (TNF-alpha), a cytokine involved in lipid metabolism. Cytokine production was assessed at the single cell level by flow cytometry after a short-term stimulation of peripheral blood T cells from HIV-infected (HIV(+)) patients who were followed during 18 months of HAART. A dramatic polarization to TNF-alpha synthesis of both CD4 and CD8 T cells was observed in all patients. Because it was previously shown that TNF-alpha synthesis by T cells was highly controlled by apoptosis, concomitant synthesis of TNF-alpha and priming for apoptosis were also analyzed. The accumulation of T cells primed for TNF-alpha synthesis is related to their escape from activation-induced apoptosis, partly due to the cosynthesis of interleukin-2 (IL-2) and TNF-alpha. Interestingly, we observed that LD is associated with a more dramatic TNF-alpha dysregulation, and positive correlations were found between the absolute number of TNF-alpha CD8 T-cell precursors and lipid parameters usually altered in LD including cholesterol, triglycerides, and the atherogenic ratio apolipoprotein B (apoB)/apoA1. Observations from the study indicate that HAART dysregulates homeostasis of TNF-alpha synthesis and suggest that this proinflammatory response induced by efficient antiretroviral therapy is a risk factor of LD development in HIV(+) patients.
Ledru
E
E
Unité d'Oncologie Virale, URA CNRS 1930, Département SIDA et Rétrovirus, Institut Pasteur, Paris, France.
Christeff
N
N
Patey
O
O
de Truchis
P
P
Melchior
J C
JC
Gougeon
M L
ML
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications* / Q000188:drug therapy; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D005260:Female; D006706:Homeostasis; D006801:Humans; D008060:Lipodystrophy / Q000209:etiology* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D019380:Anti-HIV Agents; D014409:Tumor Necrosis Factor-alpha