Dynamic interaction between astrocytes and infiltrating PBMCs in context of neuroAIDS

Abstract

HIV-mediated neuropathogenesis is a multifaceted process involving several players, including resident brain cells (neurons, astrocytes, and microglia) and infiltrating cells (peripheral blood mononuclear cells (PBMCs)). We evaluated the dynamic interaction between astrocytes and infiltrating PBMCs as it impacts HIV in the CNS. We demonstrate that human primary-derived astrocytes (PDAs) predominantly secrete Wnt 1, 2b, 3, 5b, and 10b. Wnts are small secreted glycoproteins that initiate either β-catenin-dependent or independent signal transduction. The Wnt pathway plays a vital role in the regulation of CNS activities including neurogenesis, neurotransmitter release, synaptic plasticity, and memory consolidation. We show that HIV infection of PDAs altered astrocyte Wnt profile by elevating Wnts 2b and 10b. Astrocyte conditioned media (ACM) inhibited HIV replication in PBMCs by 50%. Removal of Wnts from ACM abrogated its ability to suppress HIV replication in PBMCs. Inversely, PBMCs supernatant activated PDAs, as demonstrated by a 10-fold increase in HLA-DR and a 5-fold increase in IFNγ expression, and enhanced astrocyte susceptibility to HIV by 2-fold, which was mediated by IFNγ in a Stat-3-dependent manner. Collectively, these data demonstrate a dynamic interaction between astrocytes and PBMCs, whereby astrocyte-secreted Wnts exert an anti-HIV effect on infected PBMCs and PBMCs, in turn, secrete IFNγ that enhance astrocyte susceptibility to productive HIV infection and mediate their activation.

Migration of CD8+ T Cells into the Central Nervous System Gives Rise to Highly Potent Anti-HIV CD4dimCD8bright T Cells in a Wnt Signaling–Dependent Manner

“…Depletion of IgG was used as a control throughout. Wnts depletion was confirmed by western blot (data not shown) (27). Depletion of Wnts 1, 2b, 3, and 5b from ACM abrogated the ability of the ACM to induce the CD4 dim CD8 bright T cell phenotype (Fig.…”

“…The brain, particularly astrocytes, is a rich source of Wnts (27, 32) which initiates a cascade of events to induce β-catenin expression. Given that CD4 expression on CD8 + T cells is mediated by Wnt/β-catenin signaling (18), we evaluated whether astrocytes mediate CD4 dim CD8 bright T cell expression through Wnts secretion.…”

“…5B) compared to control, suggesting that Wnts in ACM may be driving CD4 dim CD8 bright T cell expression through increased β-catenin activity. To determine if this induction is indeed mediated by Wnts in ACM, and because there are no neutralizing antibodies for Wnts, we depleted ACM of Wnt 1, Wnt 2b, Wnt 3, Wnt 5b, or Wnt 10b by magnetic immunoprecipitation, as described (27). Depletion of IgG was used as a control throughout.…”

“…The brain and especially astrocytes, which comprise 40–60% of the brain resident cells, are a rich source for Wnt ligands (27). Wnt ligands are small secreted evolutionarily conserved glycoproteins, some of which mediate a signal transduction cascade that culminates in stabilization of β-catenin and consequently its association with members of the T cell factor (TCF)/ Lymphoid Enhancer-binding Factor (LEF) transcription factors and binding to target genes to regulate gene expression (18).…”

Plasma dickkopf-related protein 1, an antagonist of the Wnt pathway, is associated with HIV-associated neurocognitive impairment

“…Dysregulation in Wnt signaling has been linked to neurodegenerative diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease[6, 7]. We established that Wnt/β-catenin is a restriction factor for HIV in astrocytes, monocytes, and T cells, and elucidated the relevant molecular mechanisms [9–14]. We also established that inhibition of β-catenin has a dramatic effect on the ability of astrocytes to scavenge for glutamate by inhibiting the expression of Excitatory Amino Acid Transporter 2 (EAAT-2/GLT-1 in rodents) and glutamine synthetase [15].…”