Endogenous cytokine production protects T cells from spontaneous apoptosis during highly active antiretroviral therapy

• Published in: HIV medicine 2002-04, Vol.3 (2), p.105-117
• Main Authors: Ensoli, F, Fiorelli, V, De Cristofaro, M, Collacchi, B, Santini Muratori, D, Alario, C, Sacco, G, Iebba, F, Aiuti, F
• Format: Article
• Language: English
• Subjects: AIDS; Antibodies, Monoclonal - immunology; Antiretroviral Therapy, Highly Active; apoptosis; Apoptosis - immunology; Cohort Studies; cytokines; Enzyme-Linked Immunosorbent Assay; HIV; HIV Infections - drug therapy; HIV Infections - immunology; Humans; In Situ Nick-End Labeling; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Interleukin-2 - biosynthesis; Interleukin-2 - immunology; Interleukin-4 - biosynthesis; Interleukin-4 - immunology; Neutralization Tests; T-Lymphocytes - metabolism; Th1; Th2; Viral Load
• ISSN: 1464-2662; 1468-1293
• DOI: 10.1046/j.1468-1293.2002.00107.x

Background The availability of therapeutic regimens that effectively interfere with HIV‐1 replication provides novel opportunities to investigate mechanisms of T‐cell depletion as well as repopulation in infected individuals. Methods Nineteen HIV‐1‐infected individuals were investigated during one‐year follow‐up of highly active retroviral therapy (HAART). The frequencies of apoptotic T cells, as determined by propidium iodide, staining, TUNEL assay and analysis of annexin V, were assessed either in the absence or in the presence of anti‐interleukin (IL)2 and anti‐IL‐4 neutralizing Ab. Spontaneous and lectin‐induced cytokine production were assessed by ELISA. Results Increments of both naive and memory CD4 and CD8 T cells during HAART are accompanied by a decrease of T‐cell apoptosis that, after 12 months of HAART, reaches normal levels. This is associated with increments of both spontaneous and activation‐induced production of IL‐2 and IL‐4 by peripheral blood mononuclear cells (PBMCs), though only the latter was found defective at enrolment. During HAART, blocking of either IL‐2 or IL‐4 production by PBMCs using neutralizing Ab restores levels of T‐cell apoptosis consistent with those determined at enrolment. These data suggest that both IL‐2 and IL‐4 produced by PBMCs during HAART provide anti‐apoptotic signals that can contribute to an increased survival of T cells and may thus play a part in long‐term immune reconstitution. Conclusions An effective viral suppression and, possibly, effects of PI on molecular targets other than viral components, can support a progressive normalization of T‐cell survival that, at least in part, depends upon the restoration of proper soluble signals. These results provide evidence of a supporting role of endogenous cytokine production in peripheral T‐cell repopulation during an effective and prolonged viral suppression. This may be relevant for the definition of immune‐intervention targets aimed at immune reconstitution in HIV‐1‐infected patients.