Gene expression patterns associated with neurological disease in human HIV infection

Pietro Paolo Sanna,Eliezer Masliah,Vez Repunte-Canonigo,Celine Lefebvre,Eliseo A Eugenin

doi:10.1371/journal.pone.0175316

Pietro Paolo Sanna, Eliezer Masliah + Show 3 more

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https://doi.org/10.1371/journal.pone.0175316

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Abstract

The pathogenesis and nosology of HIV-associated neurological disease (HAND) remain incompletely understood. Here, to provide new insight into the molecular events leading to neurocognitive impairments (NCI) in HIV infection, we analyzed pathway dysregulations in gene expression profiles of HIV-infected patients with or without NCI and HIV encephalitis (HIVE) and control subjects. The Gene Set Enrichment Analysis (GSEA) algorithm was used for pathway analyses in conjunction with the Molecular Signatures Database collection of canonical pathways (MSigDb). We analyzed pathway dysregulations in gene expression profiles of patients from the National NeuroAIDS Tissue Consortium (NNTC), which consists of samples from 3 different brain regions, including white matter, basal ganglia and frontal cortex of HIV-infected and control patients. While HIVE is characterized by widespread, uncontrolled inflammation and tissue damage, substantial gene expression evidence of induction of interferon (IFN), cytokines and tissue injury is apparent in all brain regions studied, even in the absence of NCI. Various degrees of white matter changes were present in all HIV-infected subjects and were the primary manifestation in patients with NCI in the absence of HIVE. In particular, NCI in patients without HIVE in the NNTC sample is associated with white matter expression of chemokines, cytokines and β-defensins, without significant activation of IFN. Altogether, the results identified distinct pathways differentially regulated over the course of neurological disease in HIV infection and provide a new perspective on the dynamics of pathogenic processes in the course of HIV neurological disease in humans. These results also demonstrate the power of the systems biology analyses and indicate that the establishment of larger human gene expression profile datasets will have the potential to provide novel mechanistic insight into the pathogenesis of neurological disease in HIV infection and identify better therapeutic targets for NCI.

Highlights

While the prevalence of severe HIV-associated dementia (HAD) has decreased since the introduction of combination antiretroviral therapy, milder and chronic forms of neurocognitive impairment (NCI) including asymptomatic neurocognitive impairment (ANI) and HIV-associated neurocognitive disorders (HAND) as well as HIV-associated major depressive disorder remain high [1,2,3,4,5,6,7]
We further checked the expression of markers of neurons (RBFOX3) and oligodendrocytes (MBP) to validate the brain region profiled for white matter and frontal cortex samples, and excluded 2 samples that had conflicting expression according to their classification (D1 WM and D1 FC)
The National NeuroAIDS Tissue Consortium (NNTC) dataset was interrogated for pathway enrichment using the canonical pathways from the Molecular Signatures Database collection of canonical pathways (MSigDb) C2 collection and the Gene Set Enrichment Analysis (GSEA) algorithm [28] (See methods)

Summary

Introduction

While the prevalence of severe HIV-associated dementia (HAD) has decreased since the introduction of combination antiretroviral therapy (cART), milder and chronic forms of neurocognitive impairment (NCI) including asymptomatic neurocognitive impairment (ANI) and HIV-associated neurocognitive disorders (HAND) as well as HIV-associated major depressive disorder remain high [1,2,3,4,5,6,7]. NCI in the setting of cART is associated with synaptodendritic degeneration [7, 11, 12]. While the brain represents a sanctuary where HIV can persist due to suboptimal penetration of antiretroviral drugs [13], various studies highlighted the occurrence of NCI even in the setting of viral suppression [14, 15].

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Conclusion