Background:  Administration of interleukin (IL) -2 to HIV-infected patients leads to substantial increases in CD4 T cell counts. We have previously shown that IL-2 therapy induces increased proliferation as well as survival of CD4 T cells. In the current study, deuterium labeling was utilized to determine whether CD4 proliferation or survival was the critical determinant of IL-2-induced CD4 increases.

Methods:  We recruited 31 HIV-1-infected subjects who were on ART and receiving intermittent IL-2 therapy as part of other protocols. IL-2 therapy was administered by subcutaneous injection (3.0 – 7.5 IU daily for 5 days), and deuterated glucose was administered by continuous infusion over 5 days (60 g/day). Lymphocyte subsets were examined by flow cytometry. Deuterium enrichment was determined by liquid or gas chromatography–mass spectrometry. A previously developed model was used to describe label decay kinetics, including mean log disappearance rate of the fraction of labeled cells (m_d). Associations between kinetic parameters and cell count changes were examined using Spearman correlation and simple and multiple linear regression.

Results:  The mean baseline CD4 count was 638 cells/µL, and the mean viral load was 5560 copies/mL. The mean CD4 count increase was +249 cells/µL and mean m_d for CD4s was –1.41. A highly significant inverse correlation was seen between change in CD4 T cell numbers and m_d (R = –0.67; p <0.001). A similar correlation was not seen with CD8 T cells, or with other kinetic parameters, including the number of proliferating cells. Linear regression showed that a one unit decrease in m_d (or a 10-fold increase in half-life) was associated with a mean increase in CD4 count of 209 cells/µL (SE = 48; p <0.01). Other factors were examined for association with CD4 count increase in simple and multiple linear regression models. These factors included baseline total CD4 and naïve CD4 counts, viral load, activated CD4s, and CD4 expressing CD25. Although the baseline CD4 T cell count and number of CD4 cells expressing CD25 were also predictive of CD4 T cell increases, the decay rate remained the most statistically significant predictor in multivariate regression models.

Conclusions:  Increase in survival of CD4 T cells appears to be the critical mechanism by which IL-2 leads to sustained CD4 cell increases in HIV-infected patients receiving intermittent IL-2 therapy.