Neuronal Stress and Injury Caused by HIV-1, cART and Drug Abuse: Converging Contributions to HAND

Sánchez, Ana B.; Kaul, Marcus

doi:10.3390/brainsci7030025

Cited by 41 publications

(33 citation statements)

References 242 publications

(380 reference statements)

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“…Malignancies, depression, and immune dysfunctions are specifically linked to cognitive and behavioral abnormalities as are antiretroviral drugs (ARVs) themselves. The latter plays a role in direct neurotoxicity and consequent neuropsychiatric compromise [ 6 , 7 ]. Among them, to date, efavirenz is known to affect neuronal function [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Nanoformulated Antiretroviral Therapy Attenuates Brain Metabolic Oxidative Stress

et al. 2018

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Antiretroviral therapy (ART) restricts human immunodeficiency virus type one (HIV-1) replication and by so doing, improves the quality and longevity of life for infected people. Nonetheless, treatment can also lead to adverse clinical outcomes such as drug resistance and systemic adverse events. Both could be affected by long-acting slow effective release ART. Indeed, maintenance of sustained plasma drug levels, for weeks or months, after a single high-level dosing, could improve regimen adherence but, at the same time, affect systemic toxicities. Of these, the most troubling are those that affect the central nervous system (CNS). To address this, dolutegravir (Tivicay, DTG), a potent and durable HIV integrase inhibitor used effectively in combination ART was tested. Rodents were administered parenteral 45-mg/kg doses. DTG-associated changes in CNS homeostasis were assessed by measuring brain metabolic activities. After antiretroviral treatment, brain subregions were dissected and screened by mass spectrometry-based metabolomics. Metabolic drug-related dysregulation of energy and oxidative stress were readily observed within the cerebellum and frontal cortex following native drug administrations. Each was associated with alterations in neural homeostasis and depleted canonical oxidation protection pools that included glutathione and ascorbic acid. Surprisingly, the oxidative stress-related metabolites were completely attenuated when DTG was administered as nanoformulations. These data demonstrate the importance of formulation design in control of DTG or perhaps other antiretroviral drug-associated CNS events.

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Section: Introductionmentioning

confidence: 99%

Nanoformulated Antiretroviral Therapy Attenuates Brain Metabolic Oxidative Stress

et al. 2018

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“…In HIV studies, degree of neurocognitive impairment has been shown to correlate with reduced NAA levels [ 32 ]. Although neuronal apoptosis has been observed in brains of individuals with HAND [ 62 , 63 ], the general consensus is that prolonged neuronal dysfunction precipitates permanent neuronal loss. Reversible alterations in synaptodendritic networks have been demonstrated in the setting of HIV infection [ 16 , 64 ], and damage to these structures is a strong pathological correlate of neurocognitive impairment due to HIV [ 33 , 65 ].…”

Section: Discussionmentioning

confidence: 99%

Temporal/compartmental changes in viral RNA and neuronal injury in a primate model of NeuroAIDS

González

Fell

et al. 2018

PLoS ONE

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Despite the advent of highly active anti-retroviral therapy HIV-associated neurocognitive disorders (HAND) continue to be a significant problem. Furthermore, the precise pathogenesis of this neurodegeneration is still unclear. The objective of this study was to examine the relationship between infection by the simian immunodeficiency virus (SIV) and neuronal injury in the rhesus macaque using in vivo and postmortem sampling techniques. The effect of SIV infection in 23 adult rhesus macaques was investigated using an accelerated NeuroAIDS model. Disease progression was modulated either with combination anti-retroviral therapy (cART, 4 animals) or minocycline (7 animals). Twelve animals remained untreated. Viral loads were monitored in the blood and cerebral spinal fluid, as were levels of activated monocytes in the blood. Neuronal injury was monitored in vivo using magnetic resonance spectroscopy. Viral RNA was quantified in brain tissue of each animal postmortem using reverse transcription polymerase chain reaction (RT-PCR), and neuronal injury was assessed by immunohistochemistry. Without treatment, viral RNA in plasma, cerebral spinal fluid, and brain tissue appears to reach a plateau. Neuronal injury was highly correlated both to plasma viral levels and a subset of infected/activated monocytes (CD14+CD16+), which are known to traffic the virus into the brain. Treatment with either cART or minocycline decreased brain viral levels and partially reversed alterations in in vivo and immunohistochemical markers for neuronal injury. These findings suggest there is significant turnover of replicating virus within the brain and the severity of neuronal injury is directly related to the brain viral load.

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“…Drug abuse and addiction can cause a greater neurocognitive impairment and poorer HAART adherence compared to non-drug users [3,27,38]. Indeed, HAART slows down the progression of HIV to AIDS, and so incomplete adherence can lead to immunosuppression and drug resistant HIV [34], while non-adherence increases HIV-related morbidity and mortality.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the use of recreational drugs have been found to induce CNS impairment independent of the effects of HIV infection [3]. Consequently, people living with HIV/AIDS face an additional burden of psychiatric comorbidity, where approximately 40% of patients with HIV infection will develop CNS involvement [4].…”

Section: Introductionmentioning

confidence: 99%

Is the History of Substance Abuse Correlated with Neuropsychiatric Disorders and Co-morbid HIV Infection? An Urban Population Study

Bassey¹,

Chapman²,

Pessu³

et al. 2018

J Neurol Neurosci

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Background Human immunodeficiency virus (HIV) infection remains a serious immunological disease with new infections in the U.S. disproportionately reported in minority populations. For many years, the District of Columbia (DC) has reported the highest HIV infection rate in the nation. Drug abuse and addiction is also prevalent in DC and has traditionally been linked to HIV/AIDS because of the likelihood for opportunistic infections. Despite this data, the relationship between HIV status, drugs of abuse, and the incidence of neurological disorders are scarcely reported for minority populations. Method We carried out a retrospective study on the prevalence of substance abuse in HIV and their association with neuropsychiatric comorbidities in an African American subpopulation in Washington DC. Findings Our data suggests an 86 percent prevalence of drug use in the HIV patients with neuropsychiatric comorbidities, with cocaine use being significantly higher in patients with major depressive disorder (MDD) and bipolar disorder (BD), whereas PCP use was associated with patients with schizophrenia. The mean CD4 count was elevated in patients with neuropsychiatric disease, and specifically in MDD patients. CD8 counts were elevated as expected for HIV status but were not influenced by disease diagnosis. A majority (2/3) of patients were on HAART therapy, however the records did not account for adherence. Conclusion These data suggest that neuropsychiatric comorbidities are independent of HIV disease progression but are correlated with certain illicit drugs of abuse.

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Neuronal Stress and Injury Caused by HIV-1, cART and Drug Abuse: Converging Contributions to HAND

Cited by 41 publications

References 242 publications

Nanoformulated Antiretroviral Therapy Attenuates Brain Metabolic Oxidative Stress

Nanoformulated Antiretroviral Therapy Attenuates Brain Metabolic Oxidative Stress

Temporal/compartmental changes in viral RNA and neuronal injury in a primate model of NeuroAIDS

Is the History of Substance Abuse Correlated with Neuropsychiatric Disorders and Co-morbid HIV Infection? An Urban Population Study

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