Valeria Avdoshina1, Matthew Mahoney1,2, Sean F Gilmore3, Erin D Wenzel1,4, Albert Anderson5, Scott L Letendre6, Tomozumi Imamichi7, Nicholas O Fischer3, Italo Mocchetti1. 1. Laboratory of Preclinical Neurobiology, Department of Neuroscience. 2. Master Program in Integrative Neuroscience, Georgetown University, Washington, DC. 3. Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California. 4. Department of Pharmacology and Physiology, Georgetown University, Washington, DC. 5. Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia. 6. Departments of Medicine and Psychiatry, University of California, San Diego, La Jolla, California. 7. Frederick National Laboratory for Cancer Research, National Institute of Health, Frederick, Maryland, USA.
Abstract
OBJECTIVE: Postmortem brains of patients diagnosed with HIV-1-associated neurocognitive disorders (HAND) exhibit loss of dendrites. However, the mechanisms by which synapses are damaged are not fully understood. DESIGN: Dendrite length and remodeling occurs via microtubules, the dynamics of which are regulated by microtubule-binding proteins, including microtubule-associated protein 2 (MAP2). The HIV protein gp120 is neurotoxic and interferes with neuronal microtubules. We measured MAP2 concentrations in human cerebrospinal fluid (CSF) and MAP2 immunoreactivity in rat cortical neurons exposed to HIV and gp120. METHODS: First, we examined whether HIV affects MAP2 levels by analyzing the CSF of 27 persons living with HIV (PLH) whose neurocognitive performance had been characterized. We then used rat cortical neurons to study the mechanisms of HIV-mediated dendritic loss. RESULTS: PLH who had HAND had greater MAP2 concentrations within the CSF than cognitive normal PLH. In cortical neurons, the deleterious effect of HIV on MAP2-positive dendrites occurred through a gp120-mediated mechanism. The neurotoxic effect of HIV was blocked by a CCR5 antagonist and prevented by Helix-A, a peptide that displaces gp120 from binding to microtubules, conjugated to a nanolipoprotein particle delivery platform. CONCLUSION: Our findings support that HIV at least partially effects its neurotoxicity via neuronal cytoskeleton modifications and provide evidence of a new therapeutic compound that could be used to prevent the HIV-associated neuropathology.
OBJECTIVE: Postmortem brains of patients diagnosed with HIV-1-associated neurocognitive disorders (HAND) exhibit loss of dendrites. However, the mechanisms by which synapses are damaged are not fully understood. DESIGN: Dendrite length and remodeling occurs via microtubules, the dynamics of which are regulated by microtubule-binding proteins, including microtubule-associated protein 2 (MAP2). The HIV protein gp120 is neurotoxic and interferes with neuronal microtubules. We measured MAP2 concentrations in human cerebrospinal fluid (CSF) and MAP2 immunoreactivity in rat cortical neurons exposed to HIV and gp120. METHODS: First, we examined whether HIV affects MAP2 levels by analyzing the CSF of 27 persons living with HIV (PLH) whose neurocognitive performance had been characterized. We then used rat cortical neurons to study the mechanisms of HIV-mediated dendritic loss. RESULTS: PLH who had HAND had greater MAP2 concentrations within the CSF than cognitive normal PLH. In cortical neurons, the deleterious effect of HIV on MAP2-positive dendrites occurred through a gp120-mediated mechanism. The neurotoxic effect of HIV was blocked by a CCR5 antagonist and prevented by Helix-A, a peptide that displaces gp120 from binding to microtubules, conjugated to a nanolipoprotein particle delivery platform. CONCLUSION: Our findings support that HIV at least partially effects its neurotoxicity via neuronal cytoskeleton modifications and provide evidence of a new therapeutic compound that could be used to prevent the HIV-associated neuropathology.
Authors: L Ratner; W Haseltine; R Patarca; K J Livak; B Starcich; S F Josephs; E R Doran; J A Rafalski; E A Whitehorn; K Baumeister Journal: Nature Date: 1985 Jan 24-30 Impact factor: 49.962
Authors: Alex K Bryant; Ronald J Ellis; Anya Umlauf; Ben Gouaux; Virawudh Soontornniyomkij; Scott L Letendre; Cristian L Achim; Eliezer Masliah; Igor Grant; David J Moore Journal: AIDS Date: 2015-01-28 Impact factor: 4.177
Authors: Hailong Li; Kristen A McLaurin; Charles F Mactutus; Benjamin Likins; Wenfei Huang; Sulie L Chang; Rosemarie M Booze Journal: Viruses Date: 2022-06-10 Impact factor: 5.818