4.6 Article

Macrophage Migration Inhibitory Factor (MIF) Promotes Increased Proportions of the Highly Permissive Th17-like Cell Profile during HIV Infection

Journal

VIRUSES-BASEL
Volume 14, Issue 10, Pages -

Publisher

MDPI
DOI: 10.3390/v14102218

Keywords

HIV; MIF; MDM; CD4TL co-culture; immune pathogenesis

Categories

Funding

  1. Agencia Nacional de Promocion Cientifica y Tecnologica, ANPCyT [PICT2016-1636, PICT2020-03385]

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In this study, the role of the MIF/CD74 axis in CD4(+) T lymphocytes during HIV infection was evaluated. The results suggest that MIF stimulation may contribute to viral pathogenesis by generating a microenvironment enriched in activating mediators and Th17-like CD4TLs. These findings establish a basis for considering MIF as a possible therapeutic target.
In this study, we evaluate the role of the MIF/CD74 axis in the functionality of CD4(+) T lymphocytes (CD4TL) during HIV infection. MDMs from healthy donors were infected with a R5-tropic or Transmitted/Founder (T/F) HIV strain. At day 11 post-MDM infection, allogeneic co-cultures with uninfected CD4TLs plus MIF stimulus were performed. Cytokine production was evaluated by ELISA. MIF plasma levels of people with HIV (PWH) were evaluated by ELISA. The phenotype and infection rate of CD4TLs from PWH were analyzed after MIF stimulus. Intracellular cytokines and transcription factors were evaluated by flow cytometry. Data were analyzed by parametric or non-parametric methods. The MIF stimulation of HIV-infected MDMs induced an increased expression of IL-6, IL-1 beta and IL-8. In CD4TL/MDM co-cultures, the MIF treatment increased IL-17A/ROR gamma t-expressing CD4TLs. Higher concentrations of IL-17A in supernatants were also observed. These results were recapitulated using transmitted/founder (T/F) HIV-1 strains. The MIF treatment appeared to affect memory CD4TLs more than naive CD4TLs. MIF blocking showed a negative impact on IL17A(+)CD4TL proportions. Higher MIF concentrations in PWH-derived plasma were correlated with higher IL-17A(+)CD4TL percentages. Finally, MIF stimulation in PWH-derived PBMCs led to an increase in Th17-like population. MIF may contribute to viral pathogenesis by generating a microenvironment enriched in activating mediators and Th17-like CD4TLs, which are known to be highly susceptible to HIV-1 infection and relevant to viral persistence. These observations establish a basis for considering MIF as a possible therapeutic target.

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