Vorinostat positively regulates synaptic plasticity genes expression and spine density in HIV infected neurons: role of nicotine in progression of HIV-associated neurocognitive disorder

Abstract

BackgroundHIV-associated neurocognitive disorder (HAND) is characterized by development of cognitive, behavioral and motor abnormalities, and occurs in approximately 50% of HIV infected individuals. In the United States, the prevalence of cigarette smoking ranges from 35-70% in HIV-infected individuals compared to 20% in general population. Cognitive impairment in heavy cigarette smokers has been well reported. However, the synergistic effects of nicotine and HIV infection and the underlying mechanisms in the development of HAND are unknown.ResultsIn this study, we explored the role of nicotine in the progression of HAND using SK-N-MC, a neuronal cell line. SK-N-MC cells were infected with HIV-1 in the presence or absence of nicotine for 7 days. We observed significant increase in HIV infectivity in SK-N-MC treated with nicotine compared to untreated HIV-infected neuronal cells. HIV and nicotine synergize to significantly dysregulate the expression of synaptic plasticity genes and spine density; with a concomitant increase of HDAC2 levels in SK-N-MC cells. In addition, inhibition of HDAC2 up-regulation with the use of vorinostat resulted in HIV latency breakdown and recovery of synaptic plasticity genes expression and spine density in nicotine/HIV alone and in co-treated SK-N-MC cells. Furthermore, increased eIF2 alpha phosphorylation, which negatively regulates eukaryotic translational process, was observed in HIV alone and in co-treatment with nicotine compared to untreated control and nicotine alone treated SK-N-MC cells.ConclusionsThese results suggest that nicotine and HIV synergize to negatively regulate the synaptic plasticity gene expression and spine density and this may contribute to the increased risk of HAND in HIV infected smokers. Apart from disrupting latency, vorinostat may be a useful therapeutic to inhibit the negative regulatory effects on synaptic plasticity in HIV infected nicotine abusers.

Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection

“…Synaptic plasticity is defined as a change in efficacy/strength of synapses (spine formation and maintenance of synaptic architecture) in response to the external stimuli. Neuronal plasticity dysregulation can be seen at the cellular level 4288 atluri et al by decreased spine density and synaptodendritic damage 6 and at the systemic levels with gray and white matter atrophy 7,8 in both cortical and subcortical regions. 9,10 Matrix metalloproteinases (MMPs) are a family of endopeptidases that play a major role in the degradation of most extracellular matrix proteins, wound healing, and tissue morphogenesis.…”

“…An established laboratory protocol was used for infecting the SK-N-MC cells with HIV, 6 with slight modifications. Briefly, the SK-N-MC (1×10 5 cells) cells were grown overnight in six-well plates in the Dulbecco's Modified Eagle's Medium, and these cells were activated by treating with polybrene (10 µg/mL) for 6-7 hours before the infection.…”

“…Brain macrophages and microglial cells are reported to be the key cells productively infected with HIV, and a few studies have also reported HIV infection in astrocytes, 1,2 which results in HIV-associated neurocognitive disorders (HAND). 3 Although very few reports suggest neurons being infected by HIV, [4][5][6] but postmortem studies of brains of patients with HAND show decreased synaptic plasticity/ function at various levels. Synaptic plasticity is defined as a change in efficacy/strength of synapses (spine formation and maintenance of synaptic architecture) in response to the external stimuli.…”

“…27 In our previous studies, we observed that TIMP1 is one of the highly downregulated synaptic plasticity genes in HIV-infected neuronal cells. 6 TIMP1 also acts as a neuroprotective agent in HIV infection by protecting neurons from apoptosis and by preserving the neuronal architecture. 28 However, like most proteins, TIMP1 does not cross the BBB and the native form has a short halflife (,4 hours), rapid clearance, and low bioavailability, thus limiting its application as a neuroprotecting agent for CNS diseases.…”

Sustained-release nanoART formulation for the treatment of neuroAIDS

“…19 Our group reports for the first time that vorinostat significantly activates latent HIV infection in the neuronal cells. 28 Different concentrations (0.5-5 µM) of vorinostat (solution phase) were tested for the latencybreaking ability; the results showed that a 1 µM concentration yields a significant difference in p24 value (data shown in Figure S5) and was used for the final formulation development. To confirm the efficacy of the nanoformulation after the magnetic-triggered release process after 24 hours, we conducted a p24 viral replication assay, the results of which showed ( Figure 9) that standard tenofovir (1 mg/mL solution), and MNPs-2BL nanoformulation showed equal p24 inhibition efficacy after the third day postinfection, thus suggesting that the integrity and efficacy of the drug are not lost after external magnetic application.…”