HIV and SIV Induce Alterations in CNS CaMKII Expression and Activation

Gupta, Ravi; Kelly, Kathleen M.; Helke, Kristi L.; Queen, Suzanne E.; Karper, Jami M.; Dorsey, Jamie L.; Brice, Alexis; Adams, Robert J.; Tarwater, Patrick M.; Kolson, Dennis L.; Mankowski, Joseph L.

doi:10.2353/ajpath.2010.090809

Cited by 17 publications

(18 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore any changes in levels or activation could have significant cognitive consequences. We previously showed alterations in CaMKIIα in both the pigtailed macaque ( Macaca nemestrina ) model used in this study and the less pathogenic rhesus macaque ( Macaca mulatta ) model (Akay et al , 2014; Gupta et al , 2010). In contrast to the pigtailed macaque model, total levels of CaMKIIα were unchanged while CaMKIIα activation was decreased in SIV-infected rhesus macaques, indicating that SIV-induced disruption of CaMKIIα could be species-, model-, and disease stage-specific.…”

Section: Discussionmentioning

confidence: 64%

“…We previously showed CaMKII dysregulation in the hippocampus and frontal cortex of SIV-infected rhesus macaques ( Macaca mulatta ) (Gupta et al , 2010). In collaboration with the Jordan-Sciutto lab, we recently showed lower levels of CaMKIIα in the frontal cortex of SIV-infected macaques treated combination antiretroviral therapy (cART) compared to both uninfected and SIV-infected, untreated controls (Akay et al , 2014).…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to the pigtailed macaque model, total levels of CaMKIIα were unchanged while CaMKIIα activation was decreased in SIV-infected rhesus macaques, indicating that SIV-induced disruption of CaMKIIα could be species-, model-, and disease stage-specific. CaMKIIα alterations have not yet been reported in human brains, however rat hippocampal cultures exposed to supernatants from HIV-infected human monocyte-derived macrophages had decreased CaMKIIα activation (Gupta et al , 2010), indicating that HIV can cause CaMKIIα dysregulation.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Combination fluconazole/paroxetine treatment is neuroprotective despite ongoing neuroinflammation and viral replication in an SIV model of HIV neurological disease

et al. 2014

Self Cite

View full text Add to dashboard Cite

Effective combined antiretroviral therapy (cART) in HIV infected patients has made HIV a treatable condition; however, debilitating HIV-associated neurocognitive disorders (HAND) can still affect up to 50% of HIV infected individuals even under cART. While cART has greatly reduced the prevalence of the most severe form of HAND, milder forms have increased in prevalence, leaving a the total proportion of HIV-infected individuals suffering from HAND relatively unchanged. In this study an in vitro drug screen identified fluconazole and paroxetine as protective compounds against HIV gp120 and Tat neurotoxicity. Using an accelerated, consistent SIV/macaque model of HIV-associated CNS disease, we tested the in vivo neuroprotective capabilities of combination fluconazole/paroxetine (FluPar) treatment. FluPar treatment protected macaques from SIV-induced neurodegeneration, as measured by neurofilament light chain in the CSF, APP accumulation in the axons, and CaMKIIα in the frontal cortex, but did not significantly reduce markers of neuroinflammation or plasma or CNS viral loads. Since HIV and SIV neurodegeneration is often attributed to accompanying neuroinflammation, this study provides proof of concept that neuroprotection can be achieved even in the face of ongoing neuroinflammation and viral replication.

show abstract

Section: Discussionmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Combination fluconazole/paroxetine treatment is neuroprotective despite ongoing neuroinflammation and viral replication in an SIV model of HIV neurological disease

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Another protein, CaMKIIa merits discussion, since previous knockout studies in mice clearly demonstrate that CaMKIIa is essential for synaptic plasticity and learning (Silva et al, 1992; Lisman et al, 2002). Further, Gupta and coworkers (2010) have reported that CaMKII expression and activation is significantly downregulated in rat hippocampal neuronal cultures treated with culture supernatant harvested from HIV-1 infected human monocyte-derived macrophages. In the same study, the authors observed that CaMKII activation was decreased in hippocampus and frontal cortex of SIV-infected macaques compared to uninfected animals (Gupta et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Tat upregulates expression of histone deacetylase-2 (HDAC2) in human neurons: Implication for HIV-associated neurocognitive disorder (HAND)

Saiyed

Gandhi

Agudelo

et al. 2011

Neurochemistry International

View full text Add to dashboard Cite

Histone deacetylases (HDACs) play a pivotal role in epigenetic regulation of transcription and homeostasis of protein acetylation in histones and other proteins involved in chromatin remodeling. Histone hypoacetylation and transcriptional dysfunction have been shown to be associated with a variety of neurodegenerative diseases. More recently, neuron specific overexpression of HDAC2 has been shown to modulate synaptic plasticity and learning behavior in mice. However, the role of HDAC2 in development of HIV-associated neurocognitive disorders (HAND) is not reported. Herein we report that HIV-1 Tat protein upregulate HDAC2 expression in neuronal cells leading to transcriptional repression of genes involved in synaptic plasticity and neuronal function thereby contributing to the progression of HAND. Our results indicate upregulation of HDAC2 by Tat treatment in dose and time dependant manner by human neuroblastoma SK-N-MC cells and primary human neurons. Further, HDAC2 overexpression was associated with concomitant downregulation in CREB and CaMKIIa genes that are known to regulate neuronal activity. These observed effects were completely blocked by HDAC2 inhibition. These results for the first time suggest the possible role of HDAC2 in development of HAND. Therefore, use of HDAC2 specific inhibitor in combination with HAART may be of therapeutic value in treatment of neurocognitive disorders observed in HIV-1 infected individuals.

show abstract

“…env, tat) and host inflammatory proteins, which cause synaptodendritic damage, neural dysfunction, and neuronal death (Alirezaei et al , 2007; Bissel et al , 2002; Everall et al , 2002; Everall et al , 2001; Lipton et al , 1995; Westmoreland et al , 1996). SIV infected rhesus macaques develop encephalitis histologically and pathophysiologically similar to HIV encephalitis (HIVE) with comparable loss of pre- and post-synaptic neuronal processes (Bissel et al , 2002; Masliah et al , 1992a; Masliah et al , 1992c; Masliah et al , 1997; Wiley et al , 1991), loss or alteration of specific neuronal subpopulations, such as parvalbumin-positive interneurons (Masliah et al , 1992b), alterations in calmodulin-dependent kinase II (CaMKII) activation (Gupta et al , 2010), and increased neuronal apoptosis (Alirezaei et al , 2007; Bissel et al , 2002; Everall et al , 2002; Everall et al , 2001; Lipton et al , 1995; Westmoreland et al , 1996). Consequently, the SIV-infected rhesus provides an important model to evaluate mechanisms of neuronal injury and repair.…”

Section: Introductionmentioning

confidence: 99%

Growth-associated protein-43 and ephrin B3 induction in the brain of adult SIV-infected rhesus macaques

et al. 2011

View full text Add to dashboard Cite

Understanding the mechanisms of neuronal regeneration and repair in the adult central nervous system is a vital area of research. Using a rhesus lentiviral encephalitis model, we sought to determine whether recovery of neuronal metabolism after injury coincides with the induction of two important markers of synaptodendritic repair: growth associated protein-43 (GAP-43) and ephrin B3. We examined whether the improvement of neuronal metabolism with combined antiretroviral therapy (cART) after simian immunodeficiency virus (SIV)-infection in rhesus macaques involved induction of GAP-43, also known as neuromodulin, and ephrin B3, both implicated in axonal pathfinding during neurodevelopment and regulation of synapse formation, neuronal plasticity, and repair in adult brain. We utilized magnetic resonance spectroscopy (MRS) to demonstrate improved neuronal metabolism in vivo in adult SIV-infected cART animals compared to untreated and uninfected controls. We then assessed levels of GAP-43, ephrin B3, and synaptophysin, a pre-synaptic marker, in three brain regions important for cognitive function, cortex, hippocampus, and putamen by quantitative real-time RT-PCR and immunohistochemistry. Here we demonstrate that 1) GAP-43 mRNA and protein are induced with SIV infection, 2) GAP-43 protein is higher in the hippocampus outer molecular layer in SIV-infected animals that received cART compared to those that did not, and 3) activated microglia and infiltrating SIV-infected macrophages express abundant ephrin B3, an important axonal guidance molecule. We propose a model whereby SIV infection triggers events that lead to induction of GAP-43 and ephrin B3, and that short-term cART results in increased magnitude of repair mechanisms especially in the hippocampus, a region known for high levels of adult plasticity.

show abstract

HIV and SIV Induce Alterations in CNS CaMKII Expression and Activation

Cited by 17 publications

References 47 publications

Combination fluconazole/paroxetine treatment is neuroprotective despite ongoing neuroinflammation and viral replication in an SIV model of HIV neurological disease

Combination fluconazole/paroxetine treatment is neuroprotective despite ongoing neuroinflammation and viral replication in an SIV model of HIV neurological disease

HIV-1 Tat upregulates expression of histone deacetylase-2 (HDAC2) in human neurons: Implication for HIV-associated neurocognitive disorder (HAND)

Growth-associated protein-43 and ephrin B3 induction in the brain of adult SIV-infected rhesus macaques

Contact Info

Product

Resources

About