Treating viruses in the brain: Perspectives from NeuroAIDS

Nicol, Melanie R.; McRae, Mary Peace

doi:10.1016/j.neulet.2021.135691

Cited by 8 publications

(13 citation statements)

References 119 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ART access to the CNS is an important public health concern as it contributes to maintenance of the brain as a viral reservoir and increases risk for neurologic sequelae, including cognitive and mood disorders in people living with HIV. While it is clear that ART enters the CNS compartment, albeit to a lower extent as compared to plasma and peripheral organs [ 7 , 100 – 111 ], the precise mechanisms at the BBB that facilitate this remain poorly understood. To address this, we used primary human brain microvascular endothelial cells and primary human astrocytes to develop an in vitro model of the human BBB.…”

Section: Resultsmentioning

confidence: 99%

Cocaine regulates antiretroviral therapy CNS access through pregnane-x receptor-mediated drug transporter and metabolizing enzyme modulation at the blood brain barrier

Colón Ortiz,

Knerler,

Fridman

et al. 2024

Fluids Barriers CNS

View full text Add to dashboard Cite

Background Appropriate interactions between antiretroviral therapies (ART) and drug transporters and metabolizing enzymes at the blood brain barrier (BBB) are critical to ensure adequate dosing of the brain to achieve HIV suppression. These proteins are modulated by demographic and lifestyle factors, including substance use. While understudied, illicit substances share drug transport and metabolism pathways with ART, increasing the potential for adverse drug:drug interactions. This is particularly important when considering the brain as it is relatively undertreated compared to peripheral organs and is vulnerable to substance use-mediated damage. Methods We used an in vitro model of the human BBB to determine the extravasation of three first-line ART drugs, emtricitabine (FTC), tenofovir (TFV), and dolutegravir (DTG), in the presence and absence of cocaine, which served as our illicit substance model. The impact of cocaine on BBB integrity and permeability, drug transporters, metabolizing enzymes, and their master transcriptional regulators were evaluated to determine the mechanisms by which substance use impacted ART central nervous system (CNS) availability. Results We determined that cocaine had a selective impact on ART extravasation, where it increased FTC’s ability to cross the BBB while decreasing TFV. DTG concentrations that passed the BBB were below quantifiable limits. Interestingly, the potent neuroinflammatory modulator, lipopolysaccharide, had no effect on ART transport, suggesting a specificity for cocaine. Unexpectedly, cocaine did not breach the BBB, as permeability to albumin and 4 kDa FITC-dextran, as well as tight junction proteins and adhesion molecules remained unchanged. Rather, cocaine selectively decreased the pregnane-x receptor (PXR), but not constitutive androstane receptor (CAR). Consequently, drug transporter expression and activity decreased in endothelial cells of the BBB, including p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 4 (MRP4). Further, cytochrome P450 3A4 (CYP3A4) enzymatic activity increased following cocaine treatment that coincided with decreased expression. Finally, cocaine modulated adenylate kinases that are required to facilitate biotransformation of ART prodrugs to their phosphorylated, pharmacologically active counterparts. Conclusion Our findings indicate that additional considerations are needed in CNS HIV treatment strategies for people who use cocaine, as it may limit ART efficacy through regulation of drug transport and metabolizing pathways at the BBB.

show abstract

Section: Resultsmentioning

confidence: 99%

Cocaine regulates antiretroviral therapy CNS access through pregnane-x receptor-mediated drug transporter and metabolizing enzyme modulation at the blood brain barrier

Colón Ortiz,

Knerler,

Fridman

et al. 2024

Fluids Barriers CNS

View full text Add to dashboard Cite

show abstract

“…While ART can partially reverse the severity of the HIV-induced dysfunction in the CNS, the injure generally continues to persist. The problem likely relays on the bioavailability of the ART drugs in the brain, since they do not efficiently cross the BBB, and concentrations in the CSF are not an accurate measure of concentrations in the brain [77]. In an attempt to guide physicians, CNS penetration scores have been calculated for current ART drugs.…”

Section: Art-associated Toxicity or Virus-mediated Damage?mentioning

confidence: 99%

“…In an attempt to guide physicians, CNS penetration scores have been calculated for current ART drugs. While better scores have been correlated with more efficient suppression of CSF viral loads, and even some studies found improvement of HAND with that treatment, others could not find improvement in neurocognitive performance [77]. Differences may relate to the aforementioned disparities between drug concentration in CSF versus brain, since drug concentrations can be measured in the CSF but not in the brain, without risky invasive procedures.…”

Section: Art-associated Toxicity or Virus-mediated Damage?mentioning

confidence: 99%

“…Differences may relate to the aforementioned disparities between drug concentration in CSF versus brain, since drug concentrations can be measured in the CSF but not in the brain, without risky invasive procedures. In some of these studies, enhanced CNS penetration was actually detrimental, highlighting that long-term use of ART can also result in toxicity to the CNS [77], which can exacerbate the damage from the virus itself.…”

Section: Art-associated Toxicity or Virus-mediated Damage?mentioning

confidence: 99%

“…Therefore, the selection of the ART combination must be done carefully. Novel drugs and therapeutic approaches are needed to improve the availability of ART drugs in the brain while reducing their toxicity [39,72,77].…”

Section: Art-associated Toxicity or Virus-mediated Damage?mentioning

confidence: 99%

See 2 more Smart Citations

Neurological complications during HIV infection

Martinez-Navío

2021

Explor Neuroprot Ther

View full text Add to dashboard Cite

Early in the course of infection, human immunodeficiency virus (HIV) is able to enter the central nervous system where it stablishes a permanent reservoir. Current antiretroviral therapies do not efficiently cross the blood-brain barrier and therefore do not reach the HIV located in the central nervous system. Consequently, HIV infection can often be associated with neurocognitive impairment and HIV-associated dementia. The purpose of this review is to brief the reader into the world of neurological complications arising from HIV infection. Mechanisms by which HIV directly or indirectly impairs the central nervous system are discussed, as well as other factors influencing or contributing to the impairment, and the animal models currently used to perform research on the topic.

show abstract

NeuroHIV in the context of opioid use disorder

McRae,

Nicol

2024

HIV-Associated Neurocognitive Disorders

View full text Add to dashboard Cite

Treating viruses in the brain: Perspectives from NeuroAIDS

Cited by 8 publications

References 119 publications

Cocaine regulates antiretroviral therapy CNS access through pregnane-x receptor-mediated drug transporter and metabolizing enzyme modulation at the blood brain barrier

Cocaine regulates antiretroviral therapy CNS access through pregnane-x receptor-mediated drug transporter and metabolizing enzyme modulation at the blood brain barrier

Neurological complications during HIV infection

NeuroHIV in the context of opioid use disorder

Contact Info

Product

Resources

About