HIV-1 Tat-Mediated Induction of Platelet-Derived Growth Factor in Astrocytes: Role of Early Growth Response Gene 1

Abstract

HIV-associated neurological disorders (HAND) are estimated to affect almost 60% of HIV infected individuals. 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. Using the macaque model, it has been demonstrated that simian immunodeficiency virus encephalitis (SIVE) correlates with increased expression of the mitogen platelet-derived growth factor-B (PDGF-B) chain in the brain. The present study was aimed at exploring the role of PDGF-B chain in HIV-associated activation and proliferation of astrocytes. Specifically, the data herein demonstrate that exposure of rat and human astrocytes to the HIV-1 protein, Tat resulted in the induction of PDGF at both the mRNA and protein levels. Furthermore, PDGF-BB induction was regulated by activation of ERK1/2 and JNK signaling pathways and the downstream transcription factor, early growth response 1(Egr-1). Chromatin immunoprecipitation (ChIP) assays demonstrated binding of Egr-1 to the PDGF-B promoter. Exposure of astrocytes to PDGF-BB, in turn, led to both increased proliferation and release of pro-inflammatory cytokines MCP-1 and IL-1β. Since astrogliosis is linked to disease severity, understanding its regulation by PDGF-BB could aid in the development of therapeutic intervention strategies for HAND.

HIV Tat-Mediated Induction of Human Brain Microvascular Endothelial Cell Apoptosis Involves Endoplasmic Reticulum Stress and Mitochondrial Dysfunction

“…Toxicity of HIV Tat on various cells of the CNS has been well documented [14, 15], and it has also been shown that intraventricular injection of the viral protein in rodents results in inflammation, gliosis, apoptosis, and ventricular enlargement [16, 17], with induction of reactive oxygen species (ROS) as a possible mediator of cell damage. Recent reports have implicated induction of ER stress as a major response in various cell types including neurons, astrocytes, and macrophages/microglia in the brains of HIV-positive patients [17].…”

Tat 101-Mediated Enhancement of Brain Pericyte Migration Involves Platelet-Derived Growth Factor Subunit B Homodimer: Implications for Human Immunodeficiency Virus-Associated Neurocognitive Disorders

“…Because HIV Tat is known to induce expression of PDGF-BB in astrocytes (Bethel-Brown et al, 2011;Bethel-Brown et al, 2012) and endothelial cells (Mermis et al, 2011), we sought to examine whether pericytes also responded to HIV Tat by upregulating the expression of PDGF-BB. For this, the pericyte-like cell line (C3H/ 10T1/2) was exposed to HIV Tat101 (200 ng/ml) for varying times (1, 3, 6, 12, and 24 h), and an initial screen was done to identify the RNA levels of different PDGF chains that were expressed by real-time PCR.…”

“…Similar to glial activation by inflammatory agents, pericytes have also been shown to be activated in response to lipopolysaccharide (LPS), leading in turn to release of mediators that aid in promoting transcytosis of HIV-1 virus across the BBB (Dohgu and Banks, 2013). Because HIV proteins such as Tat are present in the host despite suppression of virus replication in treated individuals and because Tat is known to induce expression of cerebrovascular permeants such as PDGF (Bethel-Brown et al, 2011;Bethel-Brown et al, 2012), we sought to examine the modulation of PDGF-BB in pericytes exposed to HIV-1 Tat and, subsequently, to examine how this modulation affected pericyte functioning. Herein, cell culture findings were also validated ex vivo in both an HIV-1 transgenic mouse model (Dickie et al, 1991) and sections of the frontal cortex from humans with HIV-encephalitis (HIV-E).…”

Monocytes Mediate HIV Neuropathogenesis: Mechanisms that Contribute to HIV Associated Neurocognitive Disorders

“…The chemokine can be elaborated not just in response to viral infection but also by exposure to viral proteins, such as tat, which remains present in the CNS despite successful cART[84-86]. HIV tat induces astrocytic CCL2 production [87, 88], as does tat treatment of human microglia [89]. However, the effects of CCL2 may also be protective depending on the kinetics and localization of its expression within the CNS[90].…”

“…BBB compromise may also occur as a result of viral proteins[131-135], HIV infection of astrocytes[60, 136, 137], increased CCL2 production [87, 88, 138], and dysregulation of endothelial cell activation/inflammatory markers[139]. These represent additional mechanisms that may facilitate monocyte entry into the CNS of HIV infected individuals.…”