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Teriflunomide and monomethylfumarate target HIV-induced neuroinflammation and neurotoxicity

: Ambrosius, Björn; Faissner, Simon; Guse, Kirsten; Lehe, Marec von; Grunwald, Thomas; Gold, Ralf; Grewe, Bastian; Chan, Andrew

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Journal of neuroinflammation 14 (2017), Art. 51, 10 pp.
ISSN: 1742-2094 (online)
Journal Article, Electronic Publication
Fraunhofer IZI ()
HIV-associated neurocognitive disorder; HAND; glial activation; microglia; leflunomide; dimethyl fumarate

HIV-associated neurocognitive disorders (HAND) affect about 50% of infected patients despite combined antiretroviral therapy (cART). Ongoing compartmentalized inflammation mediated by microglia which are activated by HIV-infected monocytes has been postulated to contribute to neurotoxicity independent from viral replication. Here, we investigated effects of teriflunomide and monomethylfumarate on monocyte/microglial activation and neurotoxicity. Human monocytoid cells (U937) transduced with a minimal HIV-Vector were co-cultured with human microglial cells (HMC3). Secretion of pro-inflammatory/neurotoxic cytokines (CXCL10, CCL5, and CCL2: p < 0.001; IL-6: p < 0.01) by co-cultures was strongly increased compared to microglia in contact with HIV-particles alone. Upon treatment with teriflunomide, cytokine secretion was decreased (CXCL10, 3-fold; CCL2, 2.5-fold; IL-6, 2.2-fold; p < 0.001) and monomethylfumarate treatment led to 2.9-fold lower CXCL10 secretion (p < 0.001). Reduced toxicity of co-culture conditioned media on human fetal neurons by teriflunomide (29%, p < 0.01) and monomethylfumarate (27%, p < 0.05) indicated functional relevance. Modulation of innate immune functions by teriflunomide and monomethylfumarate may target neurotoxic inflammation in the context of HAND.