TY - JOUR
T1 - Osteopontin counters human immunodeficiency virus type 1–induced impairment of neurite growth through mammalian target of rapamycin and beta-integrin signaling pathways
AU - Calvez, Mathilde
AU - Hseeh, George
AU - Benzer, Simon
AU - Brown, Amanda M.
N1 - Funding Information:
We thank the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH for the HIV envelope proteins. We thank Labchan Rajbhandari for assistance with the Zeiss Axio Observer.Z1 microscope and Sheila Shaheed for assistance with image collection and Rochinelle Dongmo for assistance with western blot studies.
Funding Information:
This study was also made possible through funding from the USA National Institutes of Mental Health grant R21 MH095646, R25 MH080661, and the USA National Institutes of Neurological Disorders and Stroke R01 NS102006 awarded to A.B.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/6/15
Y1 - 2019/6/15
N2 - Despite the fact that human immunodeficiency virus type 1 (HIV-1) does not enter or replicate in neurons, its infection of a subset of resident brain glia cells (microglia and astrocytes) induces via disparate mechanisms, dysregulation of glutamate metabolism, neurotoxicity, and inflammation. Antiretroviral therapies suppress viral load, but cellular activation and release of proinflammatory factors, some of which is likely related to viral reservoirs, continue to promote a microenvironment that is injurious to neurons. However, the molecular mechanisms remain to be identified. Osteopontin (OPN) is a proinflammatory cytokine-like, extracellular matrix protein that is elevated within the brain and CSF in several neurodegenerative disorders, including HIV-associated cognitive disorder. However, the impact of elevated OPN on neuronal integrity and function in HIV-infected individuals who exhibit cognitive dysfunction remains unknown. In this study, using a neuronal cell line and primary cultures of cortical rat neurons, we identify the mammalian target of rapamycin pathway involvement in a signaling interaction between OPN-β1-integrins and the HIV-1 envelope glycoprotein, which stimulates neurite growth. These findings link for the first time HIV X4-envelope receptor engagement and osteopontin-mediated signaling through β1-integrin receptors to the mTOR pathway and alterations in the cytoskeleton of cortical neurons.
AB - Despite the fact that human immunodeficiency virus type 1 (HIV-1) does not enter or replicate in neurons, its infection of a subset of resident brain glia cells (microglia and astrocytes) induces via disparate mechanisms, dysregulation of glutamate metabolism, neurotoxicity, and inflammation. Antiretroviral therapies suppress viral load, but cellular activation and release of proinflammatory factors, some of which is likely related to viral reservoirs, continue to promote a microenvironment that is injurious to neurons. However, the molecular mechanisms remain to be identified. Osteopontin (OPN) is a proinflammatory cytokine-like, extracellular matrix protein that is elevated within the brain and CSF in several neurodegenerative disorders, including HIV-associated cognitive disorder. However, the impact of elevated OPN on neuronal integrity and function in HIV-infected individuals who exhibit cognitive dysfunction remains unknown. In this study, using a neuronal cell line and primary cultures of cortical rat neurons, we identify the mammalian target of rapamycin pathway involvement in a signaling interaction between OPN-β1-integrins and the HIV-1 envelope glycoprotein, which stimulates neurite growth. These findings link for the first time HIV X4-envelope receptor engagement and osteopontin-mediated signaling through β1-integrin receptors to the mTOR pathway and alterations in the cytoskeleton of cortical neurons.
KW - Cytoskeleton
KW - Dendrites
KW - HIV-associated neurocognitive disorder
KW - Integrins
KW - Neurons
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U2 - 10.1007/s13365-019-00729-y
DO - 10.1007/s13365-019-00729-y
M3 - Article
C2 - 30758811
AN - SCOPUS:85061603053
SN - 1355-0284
VL - 25
SP - 384
EP - 396
JO - Journal of neurovirology
JF - Journal of neurovirology
IS - 3
ER -