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

Abstract

Although the introduction of antiretroviral therapy has reduced the prevalence of severe forms of neurocognitive disorders, human immunodeficiency virus (HIV)-1-associated neurocognitive disorders were observed in 50% of HIV-infected patients globally. The blood–brain barrier is known to be impermeable to most of antiretroviral drugs. Successful delivery of antiretroviral drugs into the brain may induce an inflammatory response, which may further induce neurotoxicity. Therefore, alternate options to antiretroviral drugs for decreasing the HIV infection and neurotoxicity may help in reducing neurocognitive impairments observed in HIV-infected patients. In this study, we explored the role of magnetic nanoparticle (MNP)-bound tissue inhibitor of metalloproteinase-1 (TIMP1) protein in reducing HIV infection levels, oxidative stress, and recovering spine density in HIV-infected SK-N-MC neuroblastoma cells. We did not observe any neuronal cytotoxicity with either the free TIMP1 or MNP-bound TIMP1 used in our study. We observed significantly reduced HIV infection in both solution phase and in MNP-bound TIMP1-exposed neuronal cells. Furthermore, we also observed significantly reduced reactive oxygen species production in both the test groups compared to the neuronal cells infected with HIV alone. To observe the effect of both soluble-phase TIMP1 and MNP-bound TIMP1 on spine density in HIV-infected neuronal cells, confocal microscopy was used. We observed significant recovery of spine density in both the test groups when compared to the cells infected with HIV alone, indicting the neuroprotective effect of TIMP1. Therefore, our results suggest that the MNP-bound TIMP1 delivery method across the blood–brain barrier can be used for reducing HIV infectivity in brain tissue and neuronal toxicity in HIV-infected patients.

Advancements in nano-enabled therapeutics for neuroHIV management

“…Recently, magnetically guided delivery of an anti-inflammatory agent, namely, tissue inhibitor of metalloproteinase-1 (TIMP1), across the BBB is demonstrated to reduce HIV infection using MNPs as NCs and SK-N-MC neuroblastoma cells as in vitro model. 30 This report claimed that TIMP1 reduced neuronal toxicity and significant recovery of spinal density and thus confirmed neuroprotective effects of TIMP1 in the CNS. 30 The above discussed in vitro model showed impressive reduction in the HIV infection level across the BBB; therefore, efforts must be made to demonstrate these models in vivo to develop personalized nanomedicine to cure neuroHIV.…”

“…30 This report claimed that TIMP1 reduced neuronal toxicity and significant recovery of spinal density and thus confirmed neuroprotective effects of TIMP1 in the CNS. 30 The above discussed in vitro model showed impressive reduction in the HIV infection level across the BBB; therefore, efforts must be made to demonstrate these models in vivo to develop personalized nanomedicine to cure neuroHIV.…”

Magnetic Nanoparticles in the Central Nervous System: Targeting Principles, Applications and Safety Issues

“…applications for CNS disease: brain tumors [ 50 , 51 , 52 , 53 ], neuroAIDS [ 54 , 55 , 56 , 57 , 58 , 59 ], wireless Deep Brain Stimulation (DBS) [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ], stroke [ 68 , 69 ], NDs [ 70 , 71 , 72 , 73 , 74 , 75 ]; …”

“…Magnetic nanocarriers can be used to target hidden latent virus in the brain, but also to treat the neurological disorders caused by HIV damage to the CNS (neuroAIDS), consisting in neurocognitive impairment and HIV-associated dementia. Specifically, nanocarriers were used in vitro for delivering anti-HIV drugs to reduce infection levels and oxidative stress, but also to regulate synaptic activity and recover spine density [ 54 , 55 , 56 , 57 , 58 , 59 ].…”

Multifunctional Nanotherapeutics for the Treatment of neuroAIDS in Drug Abusers

“…The challenges of lifelong HAART include drug toxicity, the development of drug resistance, adverse drug interactions, stringent treatment adherence and high costs of treatment 4 . Along with peripheral reservoir, the central nervous system (CNS) is also a major target of HIV and is responsible for a number of neurologic disorders including neuroAIDS 5 – 7 . HIV infection of the CNS is associated with the development of asymptomatic neurocognitive impairment, HIV-associated mild neurocognitive disorder (HAND), and HIV-associated dementia (HAD) that manifest as a clinical syndrome of cognitive, motor, and behavioral dysfunction 8 .…”