MIF expression is involved in the activation of CD4+ T-cells and facilitates the infection by HIV-1

TRIFONE, C; GHIGLIONE, Y; SALIDO, J; TURK, G; CZERNIKIER, A

Mar del Plata

Congreso; SAIC-SAI-SAFIS 2018; 2018

Macrophage Migration Inhibitory Factor (MIF) plasma levels are increased in HIV+ individuals compared to healthy donors. Our group described a novel function of MIF in inflammatory processes when acting on primary HIV-1 infected MDMs. Additional evidence suggests that MIF expression might play a relevant role in the activation of CD4+ T lymphocytes (CD4TL). Aim: to identify the role of MIF in CD4TL activation and subsequent HIV-1 infection.Primary CD4TL from healthy donors were activated with PHA with or without adding a MIF-blocking antibody. Also, the effect of exogenous-added MIF on not activated CD4TL was assessed. In both conditions, expression of membrane markers were evaluated by flow cytometry. Permissiveness to HIV-1 infection was evaluated. Two reporter lines (CEM and Ghost) were stimulated with MIF to evaluate GFP expression downstream the LTR viral promoter.In primary CD4TL, MIF neutralization inhibited PHA-driven activation. A decrease in the frequency of blast like cells (16.88%) compared to PHA-activated CD4TL (50.71%) (p=0.017) was observed. Also, lower expression of membrane activation markers (CD38, CD28, HLA-DR), was found.Number of infected cells was significantly lower when blocking MIF activity (1.32%), compared to the PHA-alone control (6.58%, 0.0026), resembling results from not activated CD4TL (0.85%).MIF-stimulated not activated CD4TL showed a higher viral production after infection (95.82 ng/ml) compared to unstimulated cells (11.84 ng/ml) (p=0.022). No differences were detected in infection percentage, cell viability or activation among all conditions. Finally, LTR promoter-driven expression of GFP in reporter cell lines was unaffected by MIF. Our work depicts an important role of MIF in CD4TL activation. Intracellular MIF activity drives CD4TC activation, which in turn, promotes permissiveness to HIV-1 infection. Conversely, exogenous MIF triggered higher viral production without affecting cell activation, proliferation or infection percentage. These differences could be related to pathway signalling. Intracellular expression could trigger mechanisms unavailable to exogenous MIF due to a possible low incorporation into the cell.