Human Immunodeficiency virus -1 (HIV)-associated dementia (HAD) is characterized by a severe loss of neurons and fibers throughout the brain. It is estimated that a third of HIV-infected individuals in the USA are intravenous opiate drug abusers. It is believed that heroin, morphine and other intravenous opiate drugs may exacerbate the neurotoxic effect of HIV. However, little is known about the molecular and cellular mechanisms of this effect despite the enormous expansion of knowledge regarding the complex factors that determine slow but progressive neuronal death in these patients. Opiates, and in particular morphine, have been shown to cause abnormalities in the functioning of immune cells including microglia and to render these cells more """"""""susceptible"""""""" to HIV infection. However, experimental data have shown that morphine synergizes with HIV viral proteins in causing apoptosis even in the absence of microglia. Thus, alteration of immune/glial cells alone cannot explain loss of neurons in HAD. Chronic opiates alter the expression of chemokine receptors CCR5 and CXCR4, known to mediate the neurotoxic effect of HIV. Thus, opiates may use this cellular mechanism to amplify HIV neurotoxic property. The HIV protein gp120 reduces the levels of brain-derived neurotrophic factor BDNF (BDNF) in rat brain. BDNF is a natural modulator of chemokine receptor expression. Therefore, we propose the hypothesis that HAD derives from a multiple step interaction between opiates and HIV that causes a profound alteration of endogenous cellular mechanisms of neuroprotection and plasticity. To test this hypothesis we will first use rodents (in vitro and in vivo studies) to test the role of morphine and two strains of HIV envelop proteins gp120 on chemokine and chemokine receptors and neuronal survival. Moreover, we propose a series of comprehensive studies in human subjects aimed at establishing the role of BDNF and BDNF polymorphism on the development of HAD. Such studies include BDNF analysis of post-mortem brains of HAD subjects with a history of heroin abuse, as well as examination of a cohort of HIV infected subjects (from the Women's Interagency HIV Study cohort) for BDNF polymorphisms. We believe that lack of BDNF is a risk factor for HAD. The long term aim of this application is to establish a new mechanism of HIV opiates interaction that explains why neurons of drug abusers are more vulnerable to apoptosis than non abusers. This mechanism includes reduction of trophic support and enhancement of pro-apoptotic chemokine receptors in neurons. Proving such mechanism will help develop effective drug therapy to reverse or delay HAD.
At least a third of subjects infected with Human Immunodeficiency Virus-1 are drug abusers. The combination of infection, morphine, heroin addition (or other drugs) is believed to be toxic to the brain. This application will study the mechanisms as well as the genetic abnormalities that may be risk factors for developing brain damage in these subjects.
|Campbell, Lee A; Avdoshina, Valeriya; Day, Chris et al. (2015) Pharmacological induction of CCL5 in vivo prevents gp120-mediated neuronal injury. Neuropharmacology 92:98-107|
|Mocchetti, Italo; Bachis, Alessia; Campbell, Lee A et al. (2014) Implementing neuronal plasticity in NeuroAIDS: the experience of brain-derived neurotrophic factor and other neurotrophic factors. J Neuroimmune Pharmacol 9:80-91|
|Avdoshina, Valeriya; Mocchetti, Italo; Liu, Chenglong et al. (2013) Single-nucleotide polymorphisms in TrkB and risk for depression: findings from the women's interagency HIV study. J Acquir Immune Defic Syndr 64:138-41|
|Avdoshina, V; Bachis, A; Mocchetti, I (2013) Synaptic dysfunction in human immunodeficiency virus type-1-positive subjects: inflammation or impaired neuronal plasticity? J Intern Med 273:454-65|
|Mocchetti, Italo; Campbell, Lee A; Harry, G Jean et al. (2013) When human immunodeficiency virus meets chemokines and microglia: neuroprotection or neurodegeneration? J Neuroimmune Pharmacol 8:118-31|
|Campbell, Lee A; Avdoshina, Valeriya; Rozzi, Summer et al. (2013) CCL5 and cytokine expression in the rat brain: differential modulation by chronic morphine and morphine withdrawal. Brain Behav Immun 34:130-40|
|Bachis, Alessia; Avdoshina, Valeriya; Zecca, Luigi et al. (2012) Human immunodeficiency virus type 1 alters brain-derived neurotrophic factor processing in neurons. J Neurosci 32:9477-84|
|Mocchetti, Italo; Bachis, Alessia; Avdoshina, Valeriya (2012) Neurotoxicity of human immunodeficiency virus-1: viral proteins and axonal transport. Neurotox Res 21:79-89|
|Avdoshina, Valeriya; Becker, Jody; Campbell, Lee A et al. (2011) Neurotrophins modulate the expression of chemokine receptors in the brain. J Neurovirol 17:58-62|
|Avdoshina, Valeriya; Garzino-Demo, Alfredo; Bachis, Alessia et al. (2011) HIV-1 decreases the levels of neurotrophins in human lymphocytes. AIDS 25:1126-8|
Showing the most recent 10 out of 12 publications