Update and New Directions in Therapeutics for Neurological Complications of HIV Infections

Ellis, Ronald J.; Letendre, Scott

doi:10.1007/s13311-016-0454-2

Cited by 8 publications

(5 citation statements)

References 52 publications

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“…For instance, within the frontostriatal circuits and associated brain networks, which regions are most consistently affected in HIV (i.e., comparing HIV+ adults to HIV− controls), and neural injury to which regions is most consistently associated with neurocognitive impairment in HIV (i.e., comparing cognitively impaired HIV+ adults to cognitively normal HIV+ adults)? Addressing these questions might help to develop a “neurally‐based” model of HAND stages/severity that may have the potential to assist with HAND diagnosis, monitoring, and treatment (Ellis & Letendre, ). Currently the standard model of HAND is solely based on neurobehavioral assessment obtained with standard neuropsychology tests (Antinori et al, ; Heaton et al, ).…”

Section: Introductionmentioning

confidence: 99%

Different roles of frontal versus striatal atrophy in HIV‐associated neurocognitive disorders

Israel

Hassanzadeh‐Behbahani

Turkeltaub

et al. 2019

Human Brain Mapping

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Gray matter (GM) atrophy is frequently detected in persons living with HIV, even in the era of combination antiretroviral therapy (cART), but the specificity of regions affected remains elusive. For instance, which regions are consistently affected in HIV? In addition, atrophy at which regions is frequently associated with neurocognitive impairment in HIV? Resolving these questions can potentially help to establish the possible neural profiles of HIV‐associated neurocognitive disorders (HAND) severity, which currently is solely defined by neurobehavioral assessments. Here, we addressed these questions using a novel meta‐analysis technique, the colocalization‐likelihood estimation (CLE) technique, to quantitatively synthesize the findings of GM atrophy in HIV+ adults. Twenty‐one of 386 studies published between 1988 and November 2017 and identified in PubMed were selected, plus four identified in other resources. In the end, 25 studies (1,370 HIV+ adults, 889 HIV− controls) were included in the meta‐analysis. This technique revealed that GM atrophy in HIV+ adults was dominated by two distinct but nonexclusive profiles: frontal (including anterior cingulate cortex, [ACC]) atrophy, which was associated withHIV‐disease and consistently differentiated HIV+ adults from HIV− controls; and caudate/striatum atrophy, which was associated with neurocognitive impairment. The critical role of caudate/striatum atrophy in neurocognitive impairment was further supported by a separate data analysis, which examined the findings of correlation analyses between GM and neurocognitive performance. These results suggest that the frontal lobe and the striatum play critical but differential roles in HAND. A neural model of HAND severity was proposed with several testable predictions.

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Section: Introductionmentioning

confidence: 99%

Different roles of frontal versus striatal atrophy in HIV‐associated neurocognitive disorders

Israel

Hassanzadeh‐Behbahani

Turkeltaub

et al. 2019

Human Brain Mapping

View full text Add to dashboard Cite

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“…In the era of combined anti-retroviral therapy (cART), HIV (+) infection has transitioned from a life-threatening disease into a chronic, manageable disease owing to efficient suppression of plasma viremia with viral loads often below the threshold of detection 1 , 2 . As HIV (+) individuals on cART continue to live longer, paradoxically, the prevalence of HIV-associated comorbidities is also on a rise.…”

Section: Introductionmentioning

confidence: 99%

“…The focus therefore has shifted to examining the contribution of HIV viral proteins in mediating the pathogenesis of HIV-associated PAH 15 , 16 . Additionally, it is now well recognized that viral proteins such as transactivator of transcription (TAT), viral envelope gp120, and Nef continue to persist despite undetectable viremia in the presence of cART 1 , 2 . Role of some of these proteins has been extensively investigated for their contribution to the pathogenesis of HIV-associated PAH.…”

Section: Introductionmentioning

confidence: 99%

Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH

et al. 2018

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The incidence of pulmonary arterial hypertension (PAH) is a significant co-morbidity observed in HIV (+) individuals. Pulmonary artery smooth muscle cells (PASMCs)—key components of the arterial vessel wall that regulate vessel diameter, demonstrate increased proliferation and hypertrophy in the lungs of HIV infected individuals, underscoring the role of these cells in the pathogenesis of HIV-associated PAH. While several pathways have been implicated in enhanced proliferation of PASMCs, detailed molecular mechanism(s) underlying HIV-associated PASMC proliferation still remain elusive. In the current study, we sought to investigate the effects HIV protein transactivator of transcription (TAT)-mediated proliferation on PASMCs. In agreement with earlier findings, our results also demonstrated TAT-mediated proliferation of human PASMCs. We identified activation of a novel Notch3 signaling pathway in TAT-mediated proliferation of PASMCs. Further validation of the Notch 3 pathway was demonstrated using both pharmacological (γ-secretase inhibitor, DAPT), as well as genetic approaches (Notch3 siRNA). Vascular endothelial growth factor A (VEGF-A) was identified as a novel downstream molecule that was induced following Notch activation. Findings from in vitro studies were further validated in archived simian immunodeficiency virus (SIV)-infected monkey lung tissues. There was increased activation of Notch3 signaling as well as enhanced expression of VEGF-A in the lungs of SIV-infected macaques compared with the lungs of SIV(−) controls. Taken together, we demonstrated that HIV-TAT increased the proliferation of PASMCs via the Notch3/VEGF-A axis. Targeting the Notch3/VEGF-A axis could thus be considered a potential therapeutic approach for the treatment of HIV-associated PAH.

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“…In some patients, genotyping revealed resistance-associated mutations toward ARVs in the CSF viral population; suggesting that treatment was failing specifically in the CNS (Canestri et al 2010;Peluso et al 2012). Consequently, the CNS constitutes an HIV-1 reservoir which poses a major challenge for viral eradication (Nath 2015;Ellis and Letendre 2016;Gray et al 2016).…”

Section: Hiv-1 Infectionmentioning

confidence: 99%

Beneficial and Adverse Effects of cART Affect Neurocognitive Function in HIV-1 Infection: Balancing Viral Suppression against Neuronal Stress and Injury

Yuan

Kaul

2019

J Neuroimmune Pharmacol

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HIV-associated neurocognitive disorders (HAND) persist despite the successful introduction of combination antiretroviral therapy (cART). While insufficient concentration of certain antiretrovirals (ARV) may lead to incomplete viral suppression in the brain, many ARVs are found to cause neuropsychiatric adverse effects, indicating their penetration into the central nervous system (CNS). Several lines of evidence suggest shared critical roles of oxidative and endoplasmic reticulum stress, compromised neuronal energy homeostasis, and autophagy in the promotion of neuronal dysfunction associated with both HIV-1 infection and long-term cART or ARV use. As the lifespans of HIV patients are increased, unique challenges have surfaced. Longer lives convey prolonged exposure of the CNS to viral toxins, neurotoxic ARVs, polypharmacy with prescribed or illicit drug use, and age-related diseases. All of these factors can contribute to increased risks for the development of neuropsychiatric conditions and cognitive impairment, which can significantly impact patient well-being, cART adherence, and overall health outcome. Strategies to increase the penetration of cART into the brain to lower viral toxicity may detrimentally increase ARV neurotoxicity and neuropsychiatric adverse effects. As clinicians attempt to control peripheral viremia in an aging population of HIV-infected patients, they must navigate an increasingly complex myriad of comorbidities, pharmacogenetics, drug-drug interactions, and psychiatric and cognitive dysfunction. Here we review in comparison to the neuropathological effects of HIV-1 the available information on neuropsychiatric adverse effects and neurotoxicity of clinically used ARV and cART. It appears altogether that future cART aiming at controlling HIV-1 in the CNS and preventing HAND will require an intricate balancing act of suppressing viral replication while minimizing neurotoxicity, impairment of neurocognition, and neuropsychiatric adverse effects.

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Update and New Directions in Therapeutics for Neurological Complications of HIV Infections

Abstract: The pace of therapeutic developments in HIV presents unique challenges to the neurologist caring for patients.

Cited by 8 publications

References 52 publications

Different roles of frontal versus striatal atrophy in HIV‐associated neurocognitive disorders

Different roles of frontal versus striatal atrophy in HIV‐associated neurocognitive disorders

Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH

Beneficial and Adverse Effects of cART Affect Neurocognitive Function in HIV-1 Infection: Balancing Viral Suppression against Neuronal Stress and Injury

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