Essay Example on HIV a member of the genus Lentivirus

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Human immunodeficiency virus HIV a member of the genus Lentivirus of the family Retroviridae has become a global pandemic Campbell et al 2005 The alarming statistics surrounding HIV 1 in South Africa S A alone has shown a prevalence of 5 51 million individuals infected with HIV 1 South African National HIV 1 prevalence 2014 Evidence supports that the high rate of HIV 1 prevalence in S A is accompanied by increased antiretroviral ARV drug consumption Transer et al 2013 Despite the positive outcomes of ARV usage studies have indicated that they attribute to deleterious long term effects on the central nervous system CNS Transfer et al 2013 thus prompting further research into HIV 1 progression within the brain as well as seeking out different treatment modalities for HIV 1 patients The CNS is an important target of HIV 1 infection and its associated neurological impairment Atluri et al 2015 It comprises of glial cells macroglia and microglia and astrocytes Guduru et al 2013

These cells play an important role in processing information and maintaining the integrity of the blood brain barrier BBB within the CNS Guduru et al 2013 Ding et al 2014 The BBB consists of specialized basal micro vascular endothelial cells BMEC located on the basal lamina Abutting the basal lamina are astrocyte foot processes Bagashev and Sawaya 2013 These dendritic processes of the astrocytes extend through the tight junctions of these cells and beyond the BMEC Bagashev and Sawaya 2013 These specialized cells are integral for providing support of brain homeostasis and selective permeability of pathogenic agents Eugenin et al 2011 According to Bagashev and Sawaya 2013 HIV 1 in the brain occurs in the early stages of HIV 1 infection Since the BBB is impermeable to pathogenic agents HIV 1 makes its way into the CNS through a Trojan Horse Mechanism whereby infected immune cells pass through the BBB and into the brain Ivey et al 2009

According to Nakagawa et al 2012 endothelial cells are unable to be productively infected by HIV 1 therefore cells undergo deleterious vascular effects that are mediated by secondary mediators such as HIV 1 Tat protein Pu et al 2003 Chompre et al 2013 Tat Protein within the brain Trans activator of transcription Tat Protein one of the first regulatory proteins released by HIV 1 aids in the pathology of HIV 1 infection Campbell et al 2005 Jaegar and Nath 2012 Tat consists of a variable length of 86 104 amino acids aa and is encoded by 2 exons the first exon encodes the first 72 aa for whilst the latter encodes the remaining aa Pugliesse et al 2005 Romani et al 2010 The prominent functions of Tat consist of chromatin remodeling phosphorylation of ribose nucleic acid RNA polymerase II and transactivation of viral and cellular genes Ammosova et al 2006 Nekhai et al 2007 Ju et al 2009 Romani et al 2010 Tat protein can be successfully transported across the BBB thus making brain tissue particularly susceptible to Tat toxicity Pocernich et al 2005 Nath et al 2008 Tat has been found to be a potential contributor to HIV 1 dementia Wallace et al 2005 Ramautar et al 2012 Tat binds to BMEC of the CNS which comprise the BBB at the vascular endothelial cell growth factor receptor 2 site and is considered to be highly toxic to these cells Khan et al 2003 Atluri et al 2013 Tat elicits changes that compromise the integrity of claudins occludins and junction adhesion molecules JAMs within the BBB Gandhi et al 2010 Atluri et al 2013 Tat promotes increased secretion of intracellular Ca2 in neurons which causes the generation of reactive oxygen species

ROS activation of caspases and eventually apoptosis of neurons Huang et al 2008 Tat consequently induces oxidative stress enabling astrocytes to release monocyte chemoattractant protein 1 which promotes the regulated passage of immune cells across the BBB Fischer et al 2008 Brown 2015 The reduced permeability of the BBB allows the entry of infected migrating monocytes which activates endothelial cells and allows for binding of macrophages Pereira and Nottet 2000 Letendre 2011 Tat is subsequently released by these infected monocytes and macrophages whereby they mediate changes in the CNS through a receptor mediated pathway or direct uptake of proteins Mediouni et al 2012 The messenger Ribonucleic acid mRNA expression levels in Tat are increased in HIV 1 dementia patients causing mutations with the glutamate substitutions on the second exon of the Tat protein These mutations increase the extracellular Tat and glutamate concentrations within the brain possibly contributing to associated neurotoxic effects on the cells Pocernich et al 2005 Scottendre 2011 Tat has shown deleterious effects on hippocampal subcortical and cerebellum tissues culminating in astrocyte and microglial deregulation thus compromising neuronal function Kim et al 2003 Chang et al 2011 Nath et al 2008 introduced the phenomenon of Tat induced neurotoxicity Tat deregulates neuronal cell homeostasis through an extracellular signaling mechanism and through changes in membrane permeability and composition Croitoru Lamoury et al 2003 These changes directly impact Ca2 regulation as well as transcription and translation Schinder et al 1996 The increase in Ca2 flux impairs synaptic plasticity culminating in neuronal deregulation Penzes et al 2011 HIV 1 Tat protein mediates the subsequent release of neurotoxic substances in infected glial cells and macrophages These include viral proteins nitric oxide NO and prostaglandins Bagasra et al 1996 Capone et al 2013 Tat consequently stimulates the BMEC to secrete cytokines such as tumor necrosis factor α TNF α Inter leukin1 β IL 1 β and induces chemokine receptor expression Bagashev and Sawaya 2013 hence the toxic substances released can affect non permissive cells such as neurons Carey et al 2012 Harricharan et al 2015

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