Human Synaptic Plasticity Gene Expression Profile and Dendritic Spine Density Changes in HIV-Infected Human CNS Cells: Role in HIV-Associated Neurocognitive Disorders (HAND)

Venkata Subba Rao Atluri,Sudheesh P Kanthikeel,Adriana Yndart,Madhavan P N Nair,Pichili V B Reddy,Shilpa J Buch

doi:10.1371/journal.pone.0061399

Venkata Subba Rao Atluri, Sudheesh P Kanthikeel + Show 4 more

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https://doi.org/10.1371/journal.pone.0061399

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Journal: PloS one	Publication Date: Apr 19, 2013
Citations: 104	License type: CC BY 4.0

Affiliation: Florida International University

Abstract

HIV-associated neurocognitive disorders (HAND) is characterized by development of cognitive, behavioral and motor abnormalities, and occur in approximately 50% of HIV infected individuals. Our current understanding of HAND emanates mainly from HIV-1 subtype B (clade B), which is prevalent in USA and Western countries. However very little information is available on neuropathogenesis of HIV-1 subtype C (clade C) that exists in Sub-Saharan Africa and Asia. Therefore, studies to identify specific neuropathogenic mechanisms associated with HAND are worth pursuing to dissect the mechanisms underlying this modulation and to prevent HAND particularly in clade B infection. In this study, we have investigated 84 key human synaptic plasticity genes differential expression profile in clade B and clade C infected primary human astrocytes by using RT2 Profile PCR Array human Synaptic Plasticity kit. Among these, 31 and 21 synaptic genes were significantly (≥3 fold) down-regulated and 5 genes were significantly (≥3 fold) up-regulated in clade B and clade C infected cells, respectively compared to the uninfected control astrocytes. In flow-cytometry analysis, down-regulation of postsynaptic density and dendrite spine morphology regulatory proteins (ARC, NMDAR1 and GRM1) was confirmed in both clade B and C infected primary human astrocytes and SK-N-MC neuroblastoma cells. Further, spine density and dendrite morphology changes by confocal microscopic analysis indicates significantly decreased spine density, loss of spines and decreased dendrite diameter, total dendrite and spine area in clade B infected SK-N-MC neuroblastoma cells compared to uninfected and clade C infected cells. We have also observed that, in clade B infected astrocytes, induction of apoptosis was significantly higher than in the clade C infected astrocytes. In conclusion, this study suggests that down-regulation of synaptic plasticity genes, decreased dendritic spine density and induction of apoptosis in astrocytes may contribute to the severe neuropathogenesis in clade B infection.

Highlights

HIV is a neurotropic virus that directly invades the brain shortly after infection
Total 84 key human synaptic plasticity genes were analyzed in the RT2 Profile human Synaptic Plasticity PCR Array and fold change in the gene expression profile in clade B and clade C infected astrocytes was analyzed
In clade C infected astrocytes, total 21 synaptic plasticity genes were down-regulated compared to the control cells. It indicates that clade B is more neuropathogenic than clade C by down-regulating the more number of synaptic plasticity genes and in higher folds

Summary

Introduction

HIV replicates in brain macrophages and microglia causing inflammatory and neurotoxic host responses. HIV-1 displays wide genetic variation in global distribution. It is classified into three groups (M, O and N) and genetically into nine different subtypes (A–K). Prior to the widespread use of highly active antiretroviral therapy (HAART), 20–30% of individuals with advanced HIV-1 clade B infection displayed symptoms of the most severe HAND disorder, HIV-associated dementia (HAD) [2,3]. Satischandra et al (2000) [4] and few other studies [5] have reported unusually very low incidence-about 1– 2% of HAD in HIV-1 clade C infected patients from India. Authors have reported less neurotoxicity in clade C infected neuronal cells than clade B infected cells

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