Multivariable analysis to determine if HIV-1 Tat dicysteine motif is associated with neurodevelopmental delay in HIV-infected children in Malawi

Dara, Jasmeen; Dow, Anna; Cromwell, Elizabeth A.; Sturdevant, Christa Buckheit; Mallewa, Macpherson; Swanstrom, Ronald; Rie, Annelies Van; Prasad, Vinayaka R.

doi:10.1186/s12993-015-0083-7

Cited by 2 publications

(1 citation statement)

References 34 publications

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“…[5][6][7][8][9][10][11][12][13] Clade variances demonstrate different degrees of neuronal toxicity in vitro (reduced neurovirulence of HIV clade C vs clade B) although supporting clinical data are lacking. [14][15][16][17] In addition, efavirenz and its metabolite 8-hydroxy-efavirenz may be an additional contributor to neurocognitive impairment. [18][19][20][21] Our primary objective is to describe the neurologic phenotype in South African HIV-1 positive (subtype C) patients on antiretroviral therapy (ART) who are neurocognitively impaired.…”

Section: Registration Number Pactr201310000635418mentioning

confidence: 99%

The neurologic phenotype of South African patients with HIV-associated neurocognitive impairment

et al. 2020

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BackgroundThe neurologic manifestations of HIV include a spectrum of HIV-associated neurocognitive disorders, as well as a cluster of neurologic symptoms and signs. The neurologic manifestations have been modified but not eradicated by antiretroviral therapy (ART). We describe the neurologic phenotype in South African patients with predominant HIV-1 subtype C infection on ART and its association with neurocognitive impairment and efavirenz and 8-hydroxy-efavirenz concentrations.MethodsWe conducted a cross-sectional analysis of the neurologic examination findings of HIV+ patients with neurocognitive impairment and used multiple linear regression to explore associations with neurocognitive impairment, efavirenz, and 8-hydroxy-efavirenz pharmacokinetics (plasma and CSF).ResultsWe included 80 participants established on ART (median 40 months) of which 72 (90%) were female. The median age was 35 (interquartile range [IQR], 32-42) and the median Global Deficit Score was 0.94 (IQR 0.63-1.36). We found associations between neurocognitive impairment and neurologic signs: gait (slow walking speed [p = 0.03; R2 = 0.06], gait ataxia [p < 0.01; R2 = 0.21], and abnormal gait appearance [p < 0.01; R2 = 0.18]); coordination (upper limb bradykinesia [p < 0.01; R2 = 0.10] and lower limb bradykinesia [p = 0.01; R2 = 0.10]); reflexes (jaw jerk [p = 0.04; R2 = 0.05] and palmomental response [p = 0.03; R2 = 0.06]); ocular signs (impaired smooth pursuit [p = 0.01; R2 = 0.09] and impaired saccades [p < 0.01; R2 = 0.15]); and motor signs (spasticity [p ≤ 0.01; R2 = 0.15] and muscle weakness [p = 0.01; R2 = 0.08]). No significant associations were found between plasma and CSF efavirenz or 8-hydroxy efavirenz concentrations and any neurologic sign.ConclusionWe found that individual neurologic signs were associated with neurocognitive impairment in South African HIV+ patients with predominant HIV-1 subtype C infection on ART and could be used in clinical practice to assess severity.Registration numberPACTR201310000635418.

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Section: Registration Number Pactr201310000635418mentioning

confidence: 99%

The neurologic phenotype of South African patients with HIV-associated neurocognitive impairment

et al. 2020

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Transactivator of Transcription (Tat)-Induced Neuroinflammation as a Key Pathway in Neuronal Dysfunction: A Scoping Review

Muvenda,

Williams,

Williams

2024

Mol Neurobiol

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The activity of HIV-1 and its viral proteins within the central nervous system (CNS) is responsible for a wide array of neuropathological effects, resulting in a spectrum of neurocognitive deficits defined as HIV-associated neurocognitive disorders (HAND). Amongst the various viral proteins, the transactivator of transcription (Tat) remains detectable even with effective antiretroviral therapy (ART) and suppressed viremia, highlighting the significance of this protein in the modern ART era. Tat has been extensively researched in both fundamental and clinical settings due to its role in neuroinflammation, neuronal damage, and neurocognitive impairment amongst people living with HIV (PLHIV). To date, numerous fundamental studies have explored Tat-induced neuroinflammation. However, there is no clear consensus on the most frequently studied inflammatory markers or the consistency in the levels of these Tat-induced inflammatory marker levels across different studies. Therefore, we conducted a scoping review of studies investigating Tat-induced neuroinflammation. We conducted searches in PubMed, Scopus, and Web of Science databases using a search protocol tailored specifically to adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping reviews (PRISMA-ScR) guidelines. From the 22 included studies, findings suggest that the HIV-1 Tat protein amplifies levels of neuroinflammatory markers. Amongst the vast array of inflammatory markers explored in the included studies, consistent results point to higher levels of CCL2, IL-6, IL-8, and TNF-α in primary cells and cell lines exposed to or transfected with HIV-1 Tat. These markers are regulated by key inflammatory pathways, such as the extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, the p38 MAPK pathway, and nuclear factor-kB (NF-kB). Furthermore, Tat has been shown to induce neuronal apoptosis, both directly and indirectly. With regards to study designs, utilizing full-length Tat101 at concentrations ranging from 100 to 1000 ng/ml and durations of 24 and 48 h appears optimal for investigating Tat-induced neuroinflammation. In this context, we highlight specific inflammatory markers and pathways that are potentially pivotal in Tat-induced neuroinflammation and subsequent neuronal damage. A deeper investigation into these markers and pathways is crucial to better understand their roles in the development of HAND.

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Multivariable analysis to determine if HIV-1 Tat dicysteine motif is associated with neurodevelopmental delay in HIV-infected children in Malawi

Cited by 2 publications

References 34 publications

The neurologic phenotype of South African patients with HIV-associated neurocognitive impairment

The neurologic phenotype of South African patients with HIV-associated neurocognitive impairment

Transactivator of Transcription (Tat)-Induced Neuroinflammation as a Key Pathway in Neuronal Dysfunction: A Scoping Review

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