Involvement of Bcl-2 and IL-2R in HIV-positive patients whose CD4 cell counts fail to increase rapidly with highly active antiretroviral therapy.
OBJECTIVE
Combination antiretroviral therapy in a subset of HIV-infected patients, here called CD4-low responders (CD4-LR), fails to produce a rapid rise in CD4 cell counts despite effective control of plasma viral load (< 50 copies/ml). The mechanism responsible for this failure was investigated.


METHODS
CD4-LR patients (n = 13) included in the study had been receiving stable antiretroviral therapy for > 9 months, resulting in undetectable viral load, but nontheless showed a CD4 cell count of < 200 x 106 cells/l. Samples from these patients were analysed for intracellular expression of the anti-apoptotic molecule Bcl-2 and the in vitro apoptosis of their CD4 lymphocytes. Since interleukin-2 (IL-2) induces Bcl-2 and participates in the control of lymphocyte apoptosis, we also investigated the IL-2/IL-2 receptor (IL-2R) system in these CD4-LR patients. All these investigations were performed before and after the CD4-LR patients received IL-2 therapy.


RESULTS
CD4 T lymphocytes from these patients underexpressed the anti-apoptotic molecule Bcl-2 and were more susceptible to spontaneous apoptosis. Peripheral CD4 T lymphocytes from the CD4-LR patients showed a regulatory dysfunction in the IL-2R system that resulted in a lack of reactivity to IL-2. Overall, the results obtained with CD4-LR patients differed radically from those in patients undergoing successful antiretroviral therapy. Finally, an increase in Bcl-2 expression and IL-2 reactivity was observed in the CD4 T lymphocytes of CD4-LR patients receiving IL-2 immunotherapy. This correlated with a reduction in their apoptosis.


CONCLUSIONS
Our study characterizes the defective maintenance of peripheral CD4 T lymphocytes in CD4-LR patients, probably resulting from Bcl-2 underexpression and dysregulation of the IL-2R system.
David
Denis
D
Unité d'Immunogénétique Cellulaire, Département d'Immunologie and Centre de Recherche Clinique, Institut Pasteur, Paris, France.
Keller
Hélène
H
Naït-Ighil
Lella
L
Treilhou
Marie-Pierre
MP
Joussemet
Marcel
M
Dupont
Bertrand
B
Gachot
Bertrand
B
Maral
Jean
J
Thèze
Jacques
J
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D017209:Apoptosis; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology / Q000627:therapeutic use; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000502:physiology*
D019380:Anti-HIV Agents; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D015375:Receptors, Interleukin-2