HIV and SIV induce alterations in CNS CaMKII expression and activation: a potential mechanism for cognitive impairment.
The molecular mechanisms underlying learning and memory impairment in patients with HIV-associated neurological disease have remained unclear. Calcium/calmodulin-dependent kinase II (CaMKII) has key roles in synaptic potentiation and memory storage in neurons and also may have immunomodulatory functions. To determine whether HIV and simian immunodeficiency virus (SIV) induce alterations in CaMKII expression and/or activation (autophosphorylation) in the brain, we measured CaMKII alterations by quantitative immunoblotting in both an in vitro HIV/neuronal culture model and in vivo in an SIV-infected macaque model of HIV-associated neurological damage. Using primary rat hippocampal neuronal cultures treated with culture supernatants harvested from HIV-1-infected human monocyte-derived macrophages (HIV/MDM), we found that CaMKII activation declined after exposure of neurons to HIV/MDM. Consistent with our in vitro measurements, a significant decrease in CaMKII activation was present in both the hippocampus and frontal cortex of SIV-infected macaques compared with uninfected animals. In SIV-infected animals, total CaMKII expression in the hippocampus correlated well with levels of synaptophysin. Furthermore, CaMKII expression in both the hippocampus and frontal cortex was inversely correlated with viral load in the brain. These findings suggest that alterations in CaMKII may compromise synaptic function in the early phases of chronic neurodegenerative processes induced by HIV.
Gupta
Ravi G
RG
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
Kelly
Kathleen M
KM
Helke
Kris L
KL
Queen
Suzanne E
SE
Karper
Jami M
JM
Dorsey
Jamie L
JL
Brice
Angela K
AK
Adams
Robert J
RJ
Tarwater
Patrick M
PM
Kolson
Dennis L
DL
Mankowski
Joseph L
JL
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D005625:Frontal Lobe / Q000166:cytology / Q000201:enzymology* / Q000473:pathology / Q000821:virology*; D006678:HIV / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology* / Q000473:pathology / Q000821:virology*; D006801:Humans; D008253:Macaca mulatta / Q000378:metabolism / Q000821:virology; D009474:Neurons / Q000378:metabolism / Q000821:virology; D051381:Rats; D016097:Simian Acquired Immunodeficiency Syndrome / Q000378:metabolism; D015302:Simian Immunodeficiency Virus / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D019562:Viral Load
D016708:Synaptophysin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
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