Gene expression patterns associated with neurological disease in human HIV infection

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.

HIV‐1 Tat promotes astrocytic release of CCL2 through MMP/PAR‐1 signaling

“…Importantly, PAR-1 expression in astrocytes is elevated in the HIV encephalitis brain (Boven et al, 2003;Kim et al, 2015b). Furthermore, gene expression of a PAR-1-activating MMP has been found to be significantly dysregulated in HIV-infected brains when compared to non-infected brains (Sanna, Repunte-Canonigo, Masliah, & Lefebvre, 2017). Important to our studies, Tat alone is able to induce astrogliosis (Fan & He, 2016a, 2016bTon & Xiong, 2013;Zhou, Liu, oh, Xiao, & He, 2004) and inhibit astrocyte Wnt/β-catenin signaling (Henderson, Sharma, Monaco, Major, & Al-Harthi, 2012) which modulates HIV replication in peripheral monocytes (Richards et al, 2015).…”

“…Tat exposure resulted in a significant increase of MMP‐3 protein in astrocyte cultures (unpaired t test, df = 4, t = 7.572, p = .0016; Figure a). Notably, MMP‐13 expression has been identified as a particularly altered MMP in the HIV‐infected brain (Sanna et al, ); therefore, we focused the majority of subsequent experiments on MMP‐13. Quantitative RT‐PCR revealed Tat exposure significantly elevated MMP‐13 mRNA fold expression (unpaired t test, df = 4, t = 10.45, p < .0005; Figure b).…”

“…Tat exposure resulted in a significant increase of MMP-3 protein in astrocyte cultures (unpaired t test, df = 4, t = 7.572, p = .0016; Figure 2a). Notably, MMP-13 expression has been identified as a particularly altered MMP in the HIV-infected brain (Sanna et al, 2017); therefore, we focused the majority of subsequent experiments on MMP-13.…”

“…Importantly, PAR‐1 expression in astrocytes is elevated in the HIV encephalitis brain (Boven et al, ; Kim et al, ). Furthermore, gene expression of a PAR‐1‐activating MMP has been found to be significantly dysregulated in HIV‐infected brains when compared to non‐infected brains (Sanna, Repunte‐Canonigo, Masliah, & Lefebvre, ).…”

Systemic HIV-1 Infection Produces a Unique Glial Footprint in Humanized Mouse Brains

“…Transcriptional evaluations of two brain regions, the hippocampus and corpus callosum, demonstrated glial disease footprints in affecting antiviral human-specific immune responses. The importance of this model is underscored by specific glial transcriptional signatures that closely mirror the human disease (Gelman et al, 2012; Sanfilippo et al, 2017; Sanna et al, 2017).…”