Human immunodeficiency virus-1 (HIV) infection of the central nervous system damages synapses and promotes neuronal injury that culminates in HIV-associated neurocognitive disorders (HAND). How HIV damages synapses is still under investigation. Viral proteins, including the envelope protein gp120, have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanisms remain unclear. The balance between neuronal survival and damage is predominantly governed by neurotrophic factors, and in particular, brain-derived neurotrophic factor (BDNF) and its precursor proBDNF. proBDNF, when bound to the neurotrophin receptor p75 (p75NTR) activates a pro-apoptotic signal. We have shown that brains of HAND subjects, as well as neurons exposed to gp120, exhibit a significant increase of proBDNF, which correlates with a decreased expression of furin, a key enzyme in the processing of proBDNF. The removal of one allele of p75NTR, the receptor for proBDNF, rescues the loss of synapses seen in gp120 transgenic mice. Therefore, we hypothesize that HIV damages synapses through the ability of gp120 to increase proBDNF and therefore activating p75NTR. This is an important line of research because synaptic degeneration dysfunction has been linked to numerous neurodegenerative diseases but only preliminarily to HAND. The molecular and cellular mechanisms of how gp120 causes impairs/damages synapses remain under investigation. This application proposes a comprehensive set of experiments to test the main hypothesis. In particular (AIM 1), we will test the hypothesis that gp120 reduces furin levels by directly binding to this endoprotease. We will utilize (AIM 2) p75NTR-/- neurons and p75NTR antagonists to examine the mechanisms and signaling of gp120 neurotoxicity. We will perform behavioral studies for memory function (AIM 3) in gp120 transgenic (gp120tg) mice intercrossed with p75NTR null mice to investigate whether the removal of one allele for p75NTR rescues the memory impairment observed in gp120tg mice. Finally, (AIM 4) we will use human samples including the cerebrospinal fluid (CSF) to determine whether the levels of proBDNF are altered in different subgroups of HAND subjects. Levels of gp120 will also be measured in the CSF. These experiments might establish a correlation between levels of proBDNF, gp120 and neurocognitive impairment. We expect to provide new significant data on the role of p75NTR in HIV-mediated synaptic simplification.
In this application, we will test the hypothesis that HIV promotes degeneration of neurons through its envelope protein gp120. This viral protein triggers the release of a toxic compound termed proBDNF, which reduces synapses, through the activation of the low affinity neurotrophin receptor (p75NTR). Therefore, we propose to establish the relationship (and mechanisms) between gp120, p75NTR, and neuronal degeneration. !
|Rozzi, Summer J; Avdoshina, Valeria; Fields, Jerel A et al. (2018) Human immunodeficiency virus Tat impairs mitochondrial fission in neurons. Cell Death Discov 4:8|
|Bachis, Alessia; Campbell, Lee A; Jenkins, Kierra et al. (2017) Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor. Neurotox Res 32:509-517|
|Wenzel, Erin D; Bachis, Alessia; Avdoshina, Valeria et al. (2017) Endocytic Trafficking of HIV gp120 is Mediated by Dynamin and Plays a Role in gp120 Neurotoxicity. J Neuroimmune Pharmacol 12:492-503|
|Avdoshina, Valeria; Caragher, Seamus P; Wenzel, Erin D et al. (2017) The viral protein gp120 decreases the acetylation of neuronal tubulin: potential mechanism of neurotoxicity. J Neurochem 141:606-613|
|Rozzi, Summer J; Avdoshina, Valeria; Fields, Jerel A et al. (2017) Human Immunodeficiency Virus Promotes Mitochondrial Toxicity. Neurotox Res 32:723-733|
|Avdoshina, Valeria; Fields, Jerel Adam; Castellano, Paul et al. (2016) The HIV Protein gp120 Alters Mitochondrial Dynamics in Neurons. Neurotox Res 29:583-593|
|Bachis, Alessia; Forcelli, Patrick; Masliah, Eliezer et al. (2016) Expression of gp120 in mice evokes anxiety behavior: Co-occurrence with increased dendritic spines and brain-derived neurotrophic factor in the amygdala. Brain Behav Immun 54:170-177|
|Bachis, Alessia; Wenzel, Erin; Boelk, Allyssia et al. (2016) The neurotrophin receptor p75 mediates gp120-induced loss of synaptic spines in aging mice. Neurobiol Aging 46:160-8|
|Avdoshina, Valeria; Taraballi, Francesca; Dedoni, Simona et al. (2016) Identification of a binding site of the human immunodeficiency virus envelope protein gp120 to neuronal-specific tubulin. J Neurochem 137:287-98|
|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|
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