The control and eradication of neurological complications associated with AIDS continues to be an important goal in efforts toward improving the well-being of HIV-infected patients. The overarching goal of this new application is to explore the role of platelet-derived growth factor (PDGF)-CC in reversing synaptodendritic injury & the associated cognitive decline, both of which comprise the hallmark features of HIV-associated neurocognitive disorders (HAND). Clinically, HAND is associated with reduced quality of life, memory loss, and social & occupational disabilities. Pathologically, patients with HAND exhibit protracted forms of HIV- encephalitis (HIVE) often manifesting as subtle cognitive alterations rather than overt dementia. These patients often display neurodegenerative pathology with the involvement of cortical and subcortical regions and simplification of the synaptodendritic structure of neuronal populations in the neocortex. More importantly, reversible synaptodendritic neuronal injury is emerging as an important phenotype of HAND. Preliminary data from our lab has identified a novel factor - PDGF-C that acts as a neuroprotective agent both in vitro for dopaminergic neurons exposed to HIV proteins Tat & gp120 and, in vivo in rodent models of HAND. Furthermore, we have also demonstrated that down-regulation of this factor correlated with increased neuronal dysfunction in the brains of SIV-infected macaques/HIV-infected humans with encephalitis. We have also demonstrated that exposure to HIV Tat & gp120 resulted in loss of spines in hippocampal neurons both in cell culture as well as in vivo in a rodent model administered viral protein in the hippocampus. Intriguingly, Tat- induced spine loss was reversed by pre-exposure of neurons to PDGF-CC. Based on these findings the underlying central hypothesis of this proposal is that loss of dendritic spines & functional synapses (synaptodendritic) and the associated cognitive decline mediated by HIV proteins can be reversed by PDGF- CC, through activation of intracellular signaling pathways. The proposed hypothesis will be tested in 3 specific aims: 1) To determine the expression of synaptic damage & PDGF-CC and correlate it with glial activation in the brains of humans with HAND and in macaques with SIV-infection and ART therapy; 2) To determine the molecular mechanisms involved in PDGF-CC mediated reversal of HIV Tat/gp120-induced dendritic spine and synaptic loss & 3) To determine the neuroprotective efficacy of lentivirus (LV)-PDGF-C administered intrahippocampally in the humanized model of HAND. These studies are both novel and innovative in that the efficacy of PDGF-CC in restoring synaptic plasticity can have implications not only for HAND but also for other neurodegenerative diseases.
Neurocognitive complications of HIV are associated with reduced quality of life, memory loss, and social & occupational disabilities. Development of therapeutic strategies that can reverse the cognitive decline and the associated pathology are thus an urgent need. By carefully selecting specific antiretrovirals and supplementing them with neuroprotective agents such as PDGF-C, physicians might be able to promote CNS repair, thereby facilitating enhanced neural function and clinical neurological status.
| Sil, Susmita; Periyasamy, Palsamy; Thangaraj, Annadurai et al. (2018) PDGF/PDGFR axis in the neural systems. Mol Aspects Med 62:63-74 |
| Hu, Guoku; Yang, Lu; Cai, Yu et al. (2016) Emerging roles of extracellular vesicles in neurodegenerative disorders: focus on HIV-associated neurological complications. Cell Death Dis 7:e2481 |
