Abstract
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.
Highlights
Human immunodeficiency virus (HIV)-infected patients suffer serious complications, of which the pathogenesis of HIV-associated neurocognitive disorders (HAND) is one of the least understood
We set out to investigate the role of Teri and MMF in the context of microglial activation and neurotoxicity triggered by HIV-infected monocytes
As depicted in Additional file 1: Figure S1, the strongest secretion of CXCL10, CCL5, CCL2, and IL-6 was found in microglia in direct contact with HIV-transduced monocytoid cells (p < 0.001)
Summary
Human immunodeficiency virus (HIV)-infected patients suffer serious complications, of which the pathogenesis of HIV-associated neurocognitive disorders (HAND) is one of the least understood. One key hypothesis to explain the occurrence of HAND despite inhibition of viral replication is the “bystander hypothesis”. It postulates that microglia become activated by HIV-infected monocytes and T cells, which have entered the brain. Fumaric acid esters lead to the intranuclear translocation of nuclear factor 2 (Nrf2) They enhance the expression of anti-oxidative enzymes and decrease pro-inflammatory cytokine secretion by microglia during experimental autoimmune neuroinflammation [12, 13]. In HIV-infected macrophages in vitro, monomethylfumarate (MMF) decreases pro-inflammatory cytokine release and induces an antioxidant response [14, 15]. We set out to investigate the role of Teri and MMF in the context of microglial activation and neurotoxicity triggered by HIV-infected monocytes
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