Bulk Cytokine Production versus Frequency of Cytokine-Producing Cells in HIV1 Infection before and during HAART

Cytokine imbalances play a major role in HIV immunopathogenesis. This study analyzes simultaneously the frequency of cytokine-producing cells at the single cell level by flow cytometry and the disturbances in cytokine secretion assessed by ELISA in a cohort of asymptomatic HIV1 patients in different stages of CD4 depletion and during antiretroviral therapy (HAART). Early in the disease, there is an increased frequency of IFN-γ+ lymphocytes and bulk IFN-γ production, in parallel with a reduced proportion of IL4+ cells and IL4 secreted. The two IL4 measurements are significantly correlated. No such correlation was found for IFN-γ, which is consistent with a large variation in the amount of IFN-γ released per individual cell. Moreover, HAART was associated with a reduction to normal levels in the bulk IFN-γ secretion concomitant with a persistency of the overexpanded IFN-γ+ cell subset in the peripheral blood. This study emphasizes the importance of using a conjoint approach to assess the cytokine network in trials of antiretroviral and/or immune-based therapies to avoid missing significant effects which are possibly relevant in the clinical setting.