Key result
HIV-1 Tat combined with IFN-γ and TNF-α synergistically increased CXCL10 mRNA by nearly 4000-fold and protein levels by 2-fold in human astrocytes compared to cytokines alone.
Effect estimate: 4000-fold increase in mRNA and 2-fold increase in protein vs cytokines alone
p-value: p=<0.001
HIV-1 Tat synergizes with IFN-γ and TNF-α to upregulate the neurotoxic chemokine CXCL10 in human astrocytes via p38, Jnk, Akt, NF-κB, and STAT-1α pathways, highlighting a mechanism for HIV-associated neurological disorders.
May implicate Tat-cytokine synergy in HIV neuroinflammation; leaves open whether CXCL10 targeting alters outcomes.
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-gamma and TNF-alpha, 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-gamma and TNF-alpha, 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-kappaB and STAT-1alpha. Since CXCL10 levels are linked to disease severity, understanding its regulation could aid in the development of therapeutic intervention strategies for HAND.
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Williams et al. (2009) studied HIV-associated neurological disorders (HAND). HIV-1 Tat combined with IFN-γ and TNF-α vs. IFN-γ and TNF-α alone, HIV-1 Tat alone, or untreated cells was evaluated on CXCL10 mRNA and protein expression (4000-fold increase in mRNA and 2-fold increase in protein vs cytokines alone, p=<0.001). HIV-1 Tat combined with IFN-γ and TNF-α synergistically increased CXCL10 mRNA by nearly 4000-fold and protein levels by 2-fold in human astrocytes compared to cytokines alone.
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