Enhancement of HIV-1 spreading and persistence by MIF/CD74 interaction in primary monocyte-derived macrophages (MDM) and CD4+ T-lymphocytes (CD4TL) in vitro

RUIZ, MJ; SALOMON, H; TURK, GABRIELA; SALIDO, J; BUCALA, R; GHIGLIONE, Y; TRIFONE, C; LENG, L; QUIROGA, MF

Paris

Congreso; 9th IAS Conference on HIV Science (IAS 2017); 2017

Background: Understanding the mechanisms involved in HIV-1infection would facilitate the identification of new therapeutic targets to controlthe infection in the face of HAART limitations. CD74 membrane expression isup-regulated in infected cells during HIV-1 infection and correlates withimmune hyperactivation in HIV-infected individuals. Additionally, plasma levelof CD74 activating ligand MIF (Macrophage Migration Inhibitory Factor) isincreased in infected subjects. However, the role played by MIF/CD74 interactionin HIV pathogenesis remains unexplored. Aim: to study the effect of MIF/CD74interaction in primary HIV-infected monocyte-derived macrophages (MDMs) and CD4+T-lymphocytes (CD4TLs).Methods: CD4TL and MDMs were obtained from healthy donors.MDMs were infected, with a R5-tropic HIV-1 virus, and stimulated with MIFconcentrations ranging from 1 to 200 ng/ml. Cytokine production and Toll-likereceptor 4 (TLR4) expression were measured. Resting CD4TLs were treated withMDM supernatants or exogenous cytokines to evaluate stimulation ofpermissiveness to X4-tropic HIV-1 infection by p24 quantitation. Cell death wasmeasured by flow cytometry in infected and MIF-treated CD4TLs. Data analysiswas performed by parametric methods.Results: Treatment of infected MDMs with MIF resulted ina dose-dependent increase in IL-6, IL-8, TNF, sCD23 and sICAM production (p=0.006;p=0.013, p=0.0003, p< 0.0001, p=0.022, respectively) compared to untreatedcells. Similarly, there was a MIF-driven 2-fold increase in TLR4 expression. Byusing an anti-CD74 antibody, MIF/CD74 interaction was blocked and these effectswere reverted. Treatment of quiescent CD4TL with MIF-treated MDM-derived culturesupernatants led to an enhanced permissiveness to HIV-1 infection manifested as2-fold increase in viral production. MIF itself induced enhanced permissivenessto HIV infection in a dose-dependent manner. This effect was recapitulated byexogenous addition of IL-6, IL-8, or IL1. Moreover, MIF stimulation reducedthe percentage of necrotic cells within the HIV+ population by 50%compared to unstimulated infected cells (p=0.0006).Conclusions: These findings indicate that MIF/CD74interaction in infected MDMs contributes to the generation of an inflammatorymicroenvironment. This effect enhances resting CD4TL permissiveness to HIV infection,viral replication and spreading. Moreover, MIF also increases HIV-infected CD4TLsurvival, contributing to viral persistence. Overall, these results support a novelrole for the MIF/CD74 axis in HIV pathogenesis.