Highly active anti-retroviral therapy (ART; HAART) has had tremendous success in suppressing HIV replication and reducing HIV-associated morbidity and mortality. However, the prevalence of HIV-associated neurological disorders (NeuroAIDS) such as neuropathic pain and neurocognitive deficits remain high, even in the post ART era. This is puzzling in the perspective of low viral loads, and presents major clinical challenges. Yet, the underlying neuropathophysiological mechanism is poorly understood. Emerging evidence suggests a key role of ongoing chronic neuroinflammation in NeuroAIDS pathogenesis. Current mechanistic investigation focuses on HIV-1 toxic proteins such as gp120 and Tat in eliciting neuroinflammation. However, given the low viral loads after ART, the pathogenic significance of the proteins remains uncertain. Since HIV patients need to stay on ART for a long time, we reason that it is clinically important to test the alternative possibility: anti- retroviral therapy itself evokes neuroinflammatory responses, even though it controls HIV viral loads at a low level and suppresses virus-induced immune responses. This hypothesized therapy-induced chronic neuroinflammation, if validated, may have a profound impact on the design of future ART regimens. In this study, we will focus on the potential involvement of drugs in the current ART, especially its backbone components - nucleoside reverse transcriptase inhibitors (NRTIs). Based on extensive preliminary data, we hypothesize that NRTIs critically contribute to the chronic neuroinflammation through a mechanism that involves Wnt5a up-regulation. Specifically, our hypothesis entails that NRTIs cause Wnt5a increase in the CNS, which then stimulates astrocytes to express pro-inflammatory factors. Chronic increase of the inflammatory mediators is expected to cause NeuroAIDS-related neuronal damage. To test this hypothesis, we will characterize NRTI-induced neuroinflammation in the CNS (Aim 1), elucidate the mechanism of NRTI- induced CNS neuroinflammation (Aim 2), and determine the pathophysiological role of NRTI-induced CNS neuroinflammation in pathological pain development (Aim 3). Successful completion of these conceptually innovative studies will significantly advance our understanding of the neuropathogenic mechanisms by which NRTIs/ART may contribute to neurological disorders in HIV patients. The new findings may lead to further optimization of ART in clinical settings and the development of ART adjuvants to prevent NeuroAIDS, such as chronic pain and cognitive deficits.
Chronic neuroinflammation in the CNS is implicated in various neurological disorders in HIV-infected patients, but the etiological causes and mechanisms are still poorly understood. This project will help us better understand how the anti-retroviral therapy may contribute to this complication so that we can design effective adjuvants to prevent it.
|Yang, Yi; Liu, Xiaokang; Wu, Ting et al. (2018) Quercetin attenuates AZT-induced neuroinflammation in the CNS. Sci Rep 8:6194|
|Yuan, Subo; Shi, Yuqiang; Guo, Kaiwen et al. (2018) Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Induce Pathological Pain through Wnt5a-Mediated Neuroinflammation in Aging Mice. J Neuroimmune Pharmacol 13:230-236|
|Bae, Chilman; Wang, Jigong; Shim, Hyun Soo et al. (2018) Mitochondrial superoxide increases excitatory synaptic strength in spinal dorsal horn neurons of neuropathic mice. Mol Pain 14:1744806918797032|
|Zhang, Wenping; Shi, Yuqiang; Peng, Yanxi et al. (2018) Neuron activity-induced Wnt signaling up-regulates expression of brain-derived neurotrophic factor in the pain neural circuit. J Biol Chem 293:15641-15651|
|Tang, Shao-Jun (2017) Potential Role of Phase Separation of Repetitive DNA in Chromosomal Organization. Genes (Basel) 8:|
|Wu, Ting; Zhang, Juan; Geng, Mingxing et al. (2017) Nucleoside reverse transcriptase inhibitors (NRTIs) induce proinflammatory cytokines in the CNS via Wnt5a signaling. Sci Rep 7:4117|
|Tang, Shao-Jun (2017) New Evidence for the Theory of Chromosome Organization by Repetitive Elements (CORE). Genes (Basel) 8:|
|Ru, Wenjuan; Tang, Shao-Jun (2017) HIV-associated synaptic degeneration. Mol Brain 10:40|
|Wang, Yongdi; Liao, Jinxu; Tang, Shao-Jun et al. (2017) HIV-1 gp120 Upregulates Brain-Derived Neurotrophic Factor (BDNF) Expression in BV2 Cells via the Wnt/?-Catenin Signaling Pathway. J Mol Neurosci 62:199-208|