Mammalian microRNA: an important modulator of host-pathogen interactions in human viral infections

MicroRNAs (miRNAs), which are small non-coding RNAs expressed by almost all metazoans, have key roles in the regulation of cell differentiation, organism development and gene expression. Thousands of miRNAs regulating approximately 60æ% of the total human genome have been identified. They regulate genetic expression either by direct cleavage or by translational repression of the target mRNAs recognized through partial complementary base pairing. The active and functional unit of miRNA is its complex with Argonaute proteins known as the microRNA-induced silencing complex (miRISC). De-regulated miRNA expression in the human cell may contribute to a diverse group of disorders including cancer, cardiovascular dysfunctions, liver damage, immunological dysfunction, metabolic syndromes and pathogenic infections. Current day studies have revealed that miRNAs are indeed a pivotal component of host-pathogen interactions and host immune responses toward microorganisms. miRNA is emerging as a tool for genetic study, therapeutic development and diagnosis for human pathogenic infections caused by viruses, bacteria, parasites and fungi. Many pathogens can exploit the host miRNA system for their own benefit such as surviving inside the host cell, replication, pathogenesis and bypassing some host immune barriers, while some express pathogen-encoded miRNA inside the host contributing to their replication, survival and/or latency. In this review, we discuss the role and significance of miRNA in relation to some pathogenic viruses

Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection

Venkata Subba Rao Atluri* Rahul Dev Jayant* Sudheesh Pilakka-Kanthikeel, Gabriella Garcia, Thangavel Samikkannu, Adriana Yndart, Ajeet Kaushik, Madhavan Nair Center for Personalized Nanomedicine, Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA *These authors contributed equally to this work Abstract: Although the introduction of antiretroviral therapy has reduced the prevalence of severe forms of neurocognitive disorders, human immunodeficiency virus (HIV)-1-associated neurocognitive disorders were observed in 50% of HIV-infected patients globally. The blood–brain barrier is known to be impermeable to most of antiretroviral drugs. Successful delivery of antiretroviral drugs into the brain may induce an inflammatory response, which may further induce neurotoxicity. Therefore, alternate options to antiretroviral drugs for decreasing the HIV infection and neurotoxicity may help in reducing neurocognitive impairments observed in HIV-infected patients. In this study, we explored the role of magnetic nanoparticle (MNP)-bound tissue inhibitor of metalloproteinase-1 (TIMP1) protein in reducing HIV infection levels, oxidative stress, and recovering spine density in HIV-infected SK-N-MC neuroblastoma cells. We did not observe any neuronal cytotoxicity with either the free TIMP1 or MNP-bound TIMP1 used in our study. We observed significantly reduced HIV infection in both solution phase and in MNP-bound TIMP1-exposed neuronal cells. Furthermore, we also observed significantly reduced reactive oxygen species production in both the test groups compared to the neuronal cells infected with HIV alone. To observe the effect of both soluble-phase TIMP1 and MNP-bound TIMP1 on spine density in HIV-infected neuronal cells, confocal microscopy was used. We observed significant recovery of spine density in both the test groups when compared to the cells infected with HIV alone, indicting the neuroprotective effect of TIMP1. Therefore, our results suggest that the MNP-bound TIMP1 delivery method across the blood–brain barrier can be used for reducing HIV infectivity in brain tissue and neuronal toxicity in HIV-infected patients. Keywords: HIV, neurocognitive disorders, TIMP1, magnetic nanoparticles, blood–brain barrier, neuroprotectio

Convergent neighboring gene network shared by AIDS, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and age macular degeneration: Convergent gene networks are primarily the shared molecular pathways between networks of genes of two or more different diseases.

<p>In our case, the term neighboring is added because networks of individual diseases represent neighboring interactants of at-risk genes. The developed network revealed the involvement of immunological pathways as retrieved by geneMANIA with P< 10⁻¹⁰. The network was developed using the 10 common genes (black dots) found via Venn analysis. Few of these common genes are also seen in other neuro-disorders: Amyotrophic Lateral Sclerosis (AKT1, EGFR, & IKBKB), Glaucoma (AKT1 & EGFR), Vascular Dementia (AKT1 & IKBKB), and Migraine and Restless leg syndrome (AKT1). Narcolepsy, Creutzfeldt-Jakob disease, and Autism-autism spectrum did not share genes with these common gene sets suggesting least chance of these symptoms during neuroAIDS. Genes in grey dots represent networking genes retrieved by geneMANIA where smaller to higher grey circle sizes represents weaker to the stronger degree of connectivity/associations between two proteins. Colored connecting line between two genes/proteins indicates interactions between them (red-physical; orange-predicated, and green-genetic) and blue lines are part of pathways. Pathways involved in this gene circuit, together with the pathways involved in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181642#pone.0181642.g004" target="_blank">Fig 4</a>, suggests commonalities in the immunological basis of different neuropathogenesis.</p

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

<div><p>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.</p></div

Volcano plots of the unpaired t-tests of the mRNA expression fold change for active vs latent HIV infections in monocytes (N = 2): Volcano plot is primarily a scatter plot that is used for identification of changes in specific data sets by plotting significance value versus fold-change on the y- and x-axis respectively.

<p>Our study show differentially expressed mRNAs with statistical significance that passed Volcano Plot filtering (Fold Change > = 2.0 and P-value < = 0.05). Most mRNAs showed variations with 2 to 6 fold; nonetheless, CD14 and RPS6KA2 mRNAs were 35.62 and 76.22 fold upregulated and downregulated, respectively. The vertical lines correspond to 2.0-fold up and down and the horizontal line represents a P-value up to 0.05. So the blue triangles in the plot represent the differentially expressed mRNAs with statistical significance. This represents subsets of differentially expressed mRNAs from common convergent neighboring gene network shared by AIDS, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and age macular degeneration.</p

AIDS share common molecular pathways (genes) with different neurological disorders (please see S2 Data for details): neighboring gene network of each neurological disorder was compared (Venn Analysis) with that of AIDS to obtain their shared genes.

<p>All at-risk genes (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181642#pone.0181642.s007" target="_blank">S4 Data</a>) for Schizophrenia, major depression, Bipolar and Attention Deficit Hyperactivity Disorder overlapped with Autism spectrum and as such was not classified as a separate disease.</p

Preparation and characterization of anti-HIV nanodrug targeted to microfold cell of gut-associated lymphoid tissue

Upal Roy,1,* Hong Ding,1,* Sudheesh Pilakka-Kanthikeel,1 Andrea D Raymond,1 Venkata Atluri,1 Adriana Yndart,1 Elena M Kaftanovskaya,2 Elena Batrakova,3 Marisela Agudelo,1 Madhavan Nair1 1Center for Personalized NanoMedicine, Institute of NeuroImmune Pharmacology, Department of Immunology, 2Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA; 3UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA *These authors contributed equally to&nbsp;this work Abstract: The human immunodeficiency virus 1 (HIV-1) still remains one of the leading life-threatening diseases in the world. The introduction of highly active antiretroviral therapy has significantly reduced disease morbidity and mortality. However, most of the drugs have variable penetrance into viral reservoir sites, including gut-associated lymphoid tissue (GALT). Being the largest lymphoid organ, GALT plays a key role in early HIV infection and host&ndash;pathogen interaction. Many different treatment options have been proposed to eradicate the virus from GALT. However, it becomes difficult to deliver traditional drugs to the GALT because of its complex physiology. In this regard, we developed a polymer-based Pluronic nanocarrier containing anti-HIV drug called efavirenz (EFV) targeting Microfold cells (M-cells) in the GALT. M-cells are specialized epithelial cells that are predominantly present in the GALT. In this work, we have exploited this paracellular transport property of M-cells for targeted delivery of Pluronic nanocarrier tagged EFV, bioconjugated with anti-M-cell-specific antibodies to the GALT (nanodrug). Preliminary characterization showed that the nanodrug (EFV-F12-COOH) is of 140&nbsp;nm size with 0.3 polydispersion index, and the zeta potential of the particles was -19.38&plusmn;2.2&nbsp;mV. Further, drug dissolution study has shown a significantly improved sustained release over free drugs. Binding potential of nanodrug with M-cell was also confirmed with fluorescence microscopy and in vitro uptake and release studies. The anti-HIV activity of the nanodrug was also significantly higher compared to that of free drug. This novel formulation was able to show sustained release of EFV and inhibit the HIV-1 infection in the GALT compared to the free drug. The present study has potential for our in vivo targeted nanodrug delivery system by combining traditional enteric-coated capsule technique via oral administration. Keywords: HIV-1, drug delivery, GALT, M-cell