Background:  We have previously demonstrated that the interaction between CD26 and adenosine deaminase (CD26/ADA) mediates co-stimulatory signals in the immunological synapse. Here we report a study of whether the altered immunological synapse observed in HIV-1-infected patients is mediated at least in part by abnormalities in the CD26/ADA interaction.

Methods:  Fresh peripheral blood mononuclear cells (PBMC) from healthy or HIV-1-infected donors were immediately processed to obtain monocyte-derived dendritic cells (MDDC) in a 7-day culture period with serum-free medium plus 1% autologous serum plus interleukin-4 (IL-4) and granulocyte/macrophage colony stimulating factors (GM-CSF). ADA-co-stimulation ratio (defined as the proportion between the response with vs without the presence of ADA) was assessed on CD3-induced proliferation of monocyte-depleted PBMC and in proliferation and/or cytokine production in co-cultures of autologous antigen-pulsed MDDC and T cells. MDDC were pulsed with superantigen SEA as well as with heat-inactivated HIV-1 BaL virus in some HIV-infected subjects. HAART-treated (n = 14) and untreated (n = 16) patients in early stages of chronic infection were studied.

Results:  We first observed that HIV-1 gp120 added to cultures inhibited the CD26/ADA co-stimulatory signal that induces T-cell activation by anti-CD3 or by superantigen-pulsed autologous MDDC in healthy subjects. This effect seems to be mediated by the displacement of ADA by gp120. In HIV-1-infected patients, although ADA co-stimulation occurred, the co-stimulation ratio was highly variable both in anti-CD3-induced proliferation and co-cultures of SEA-pulsed MDDC. The higher response was observed in those patients with low viral load and relatively high CD4 counts. In addition, ADA caused a robust increase of cytokine secretion (n = 15) in co-cultures of MDDC pulsed with heat-inactivated HIV. The co-stimulation ratio in HIV patients was correlated with CD26 expression.

Conclusions:  gp120 disruption of CD26/ADA interaction could be a novel mechanism to explain at least in part the altered immunological synapse observed in HIV-1-infected patients. ADA co-stimulation seems to improve T-cell activation events, although mainly in patients with low viral load and high CD4 T-cell levels.