Common gene-network signature of different neurological disorders and their potential implications to neuroAIDS

Abstract

The neurological complications of AIDS (neuroAIDS) during the infection of human immunodeficiency virus (HIV) are symptomized by non-specific, multifaceted neurological conditions and therefore, defining a specific diagnosis/treatment mechanism(s) for this neuro-complexity at the molecular level remains elusive. Using an in silico based integrated gene network analysis we discovered that HIV infection shares convergent gene networks with each of twelve neurological disorders selected in this study. Importantly, a common gene network was identified among HIV infection, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and age macular degeneration. An mRNA microarray analysis in HIV-infected monocytes showed significant changes in the expression of several genes of this in silico derived common pathway which suggests the possible physiological relevance of this gene-circuit in driving neuroAIDS condition. Further, this unique gene network was compared with another in silico derived novel, convergent gene network which is shared by seven major neurological disorders (Alzheimer’s disease, Parkinson’s disease, Multiple Sclerosis, Age Macular Degeneration, Amyotrophic Lateral Sclerosis, Vascular Dementia, and Restless Leg Syndrome). These networks differed in their gene circuits; however, in large, they involved innate immunity signaling pathways, which suggests commonalities in the immunological basis of different neuropathogenesis. The common gene circuits reported here can provide a prospective platform to understand how gene-circuits belonging to other neuro-disorders may be convoluted during real-time neuroAIDS condition and it may elucidate the underlying–and so far unknown–genetic overlap between HIV infection and neuroAIDS risk. Also, it may lead to a new paradigm in understanding disease progression, identifying biomarkers, and developing therapies.

Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics

“…The expression of genes encoding HLA class 1 HLA-A , HLA-B , HLA-C , HLA-G , HLA-F are upregulated in response to interferon type I and II in HIVE [ 106 ]. Similarly, HLA-E was highly upregulated in patients with HAND (severity not specified) and HIVE [ 108 ], as was HLA-B [ 125 ]. In a more recent study, the HLA-DR genotype did not correlate significantly with neurocognitive functions (assessed as a global clinical rating; GCR) or histopathological markers in HIV-infected adults [ 21 ].…”

Modulatory Effects of Nicotine on neuroHIV/neuroAIDS

“…Alzheimer’s disease, PD, and HAND are common neurodegenerative diseases and have some shared pathways and dysfunctions (Tables 2 and 3). Very recently, it was discovered that neuroAIDS shares a convergent gene network with seven major neurological disorders, namely AD, PD, multiple sclerosis, age-related macular degeneration, amyotrophic lateral sclerosis, vascular dementia, and restless leg syndrome (Sagar et al 2017). Innate immunity signaling pathways are involved in all of these disorders, which suggests a commonality exists among different forms of neuropathogenesis.…”

“…Moreover, oxidative stress, neuronal death or survival, neurotransmitter release, cytokines and the inflammatory response, interleukin-5 (IL-5), IL-10, hypoxia-inducible factor 1 (HIF-1), NOD-like receptor, NF-κB, Toll-like receptor, tumor necrosis factor (TNF), mitogen-activated protein kinase (MAPK), PI3KAkt, JAK2/STAT3, extracellular signal-regulated kinase (ERK), and calcium signaling pathways are active in both AD and PD (Nunomura et al 2007; Kawamata and Shimohama 2011; Jiang et al 2016; Kori et al 2016; Hu et al 2017a; Hu et al 2017b). Between HAND and AD, multiple-gene enriched pathways or categories are shared; for example, functions related to cell growth and communication, regulation of transcription, immune response, defense response, response to stimuli, antigen presentation, immune cell activation, and synapsis transmission (Borjabad and Volsky 2012; Levine et al 2013; Sagar et al 2017). Some structural, functional, and metabolic brain abnormalities and neuropathology are shared by AD and HAND (Cohen et al 2015).…”

“…Motor, cognitive, attention, and executive-function deficits also exist among HAND and PD patients (DeVaughn et al 2015). Signaling pathways related to the immune response, cell activation, and antigen processing and presentation are shared in AIDS and PD (Sagar et al 2017). Given these many existing similarities among HAND and other neural disorders, nicotine may play similar roles in HAND, which will attenuate the effects of HIV infection on neurocognitive disorders.…”

Nose to brain delivery of antiretroviral drugs in the treatment of neuroAIDS

“…About 30–50% of AIDS patients experiences neuropsychiatric complications collectively called neuroAIDS [ 12 , 13 ]. In some cases, decreased functionality of brain and movement skills, along with behaviour and mood shifts, has been observed [ 14 ]. Collectively these abnormalities are termed as HIV associated Neurocognitive Disorder (HAND).…”