HIV-1 Tat co-operates with IFN-gamma and TNF-alpha to increase CXCL10 in human astrocytes

• Published in: PloS one 2009-05, Vol.4 (5), p.e5709
• Main Authors: Williams, Rachel, Yao, Honghong, Dhillon, Navneet K, Buch, Shilpa J
• Format: Article
• Language: English
• Subjects: Activation; AKT protein; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Blood-brain barrier; Brain; Cell Line; Chemokine CXCL10 - genetics; Chemokine CXCL10 - metabolism; Chemokines; CXCL10 protein; Cytokines; Encephalitis; HIV; HIV-1 - metabolism; Human immunodeficiency virus; Humans; Immunology/Immune Response; Infections; Infectious Diseases/HIV Infection and AIDS; Inflammation; Interferon; Interferon-gamma - pharmacology; JNK Mitogen-Activated Protein Kinases - metabolism; JNK protein; Kinases; Models, Biological; Nervous system; Neurological diseases; Neurological Disorders/Infectious Diseases of the Nervous System; Neuronal-glial interactions; Neurotoxicity; NF-kappa B - metabolism; NF-κB protein; p38 Mitogen-Activated Protein Kinases - metabolism; Pathogenesis; Physiology; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Ribonucleic acid; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; STAT1 Transcription Factor - metabolism; tat Gene Products, Human Immunodeficiency Virus - pharmacology; Tat protein; Transcription activation; Transcription factors; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-α; Up-Regulation - drug effects; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005709

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.