HIV-1 Tat Co-Operates with IFN-γ and TNF-α to Increase CXCL10 in Human Astrocytes

Abstract

HIV-associated neurological disorders (HAND) are estimated to affect 60% of the HIV infected population. HIV-encephalitis (HIVE), the pathological correlate of the most severe form of HAND is often characterized by glial activation, cytokine/chemokine dysregulation, and neuronal damage and loss. However, the severity of HIVE correlates better with glial activation rather than viral load. One of the characteristic features of HIVE is the increased amount of the neurotoxic chemokine, CXCL10. This chemokine can be released from astroglia activated with the pro-inflammatory cytokines IFN-γ and TNF-α, in conjunction with HIV-1 Tat, all of which are elevated in HIVE. In an effort to understand the pathogenesis of HAND, this study was aimed at exploring the regulation of CXCL10 by cellular and viral factors during astrocyte activation. Specifically, the data herein demonstrate that the combined actions of HIV-1 Tat and the pro-inflammatory cytokines, IFN-γ and TNF-α, result in the induction of CXCL10 at both the RNA and protein level. Furthermore, CXCL10 induction was found to be regulated transcriptionally by the activation of the p38, Jnk, and Akt signaling pathways and their downstream transcription factors, NF-κB and STAT-1α. Since CXCL10 levels are linked to disease severity, understanding its regulation could aid in the development of therapeutic intervention strategies for HAND.

Tat engagement of p38 MAP kinase and IRF7 pathways leads to activation of interferon-stimulated genes in antigen-presenting cells

“…43 Interestingly, p38 MAPK has also been implicated in the production and release of IP10 in astrocytes exposed to HIV-1 and Tat. [44][45][46] In addition, HIV-1 and Tat were reported to activate p38 MAPK in infected or stimulated neurotoxic monocytes and MDM. 47 Furthermore, p38 MAPK activation in iDC appears to be critical to the role played by these cells in the differentiation of Th17 helper T cells, which are preferentially targeted by HIV and ultimately are severely depleted, especially in the intestine.…”

Spatial and temporal activation of spinal glial cells: Role of gliopathy in central neuropathic pain following spinal cord injury in rats

“…Acutely, increased IL-1β and TNFα is reported to be a direct result of astrogliosis and microgliosis, ie., activated glial cells. For example, IL-1β induces expression of intercellular adhesion molecule-1 (ICAM-1) and TNFα alpha induces chemokine CXCL 10 and MCP-1 (monocyte chemo-attractant protein-1, also known as CCL2 and type I inflammatory monocyte), that both contributes to astrocytic activation (Ballestas et al, 1995; Gao et al, 2010; William, et al, 2009). Thus, proinflammatory cytokines are directly involved in persistent glial activation in both the acute (less than few days) and the chronic (more than 4 weeks) phases of injury via cell adhesion molecules, chemokines and chemoattractants for infiltrating immune cells.…”

HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity

“…Tat has indeed been detected in and secreted by astrocytes that are latently infected with HIV (9,25). Tat alters astrocyte growth (21,22,26) and induces expression of cytokines and chemokines in astrocytes such as MCP-1, IL-1␤, IL-6, RANTES, and CXCL10 (17,27,28), which could in turn recruit more macrophages/ monocytes and lymphocytes into the CNS (13)(14)(15)(16). Studies, including ours, have shown that astrocytes potentiate Tat neurotoxicity (16,20,22), probably through Tat-mediated transcriptional activation of glial fibrillary acidic protein (GFAP) expression (29 -31).…”