Soluble insulin receptor as a source of insulin resistance and cognitive impairment in HIV-seropositive women

Gerena, Yamil; Menéndez‐Delmestre, Raissa; Skolasky, Richard L.; Hechavarría, Rosa; Pérez, Sebastián; Hilera, Claudia; González, Claribel; Nath, Avindra; Wojna, Valerie

doi:10.1007/s13365-014-0310-2

Cited by 11 publications

(13 citation statements)

References 34 publications

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“…We previously showed that higher levels of plasma and CSF sIR full-length were associated with HAND in a population of HIV-infected women (41). In addition, we observed that plasma sIR served as a scavenger receptor through the binding of higher percentages of insulin in patients with the severe forms of HAND (42). These findings suggest that changes in plasma sIR could be associated with an asymptomatic glucose derangement and may contribute to the development of insulin resistance and HAND (41).…”

Section: Discussionmentioning

confidence: 95%

“…Soluble insulin receptor full-length (sIR-αβ, intact) levels methods were previously determined and published (41, 42). Briefly, levels were determined by incubating with an anti-IR ectodomain antibody (1:1,000) (Abcam, Cambridge, MA) for 2 h at 20°C and a FITC-secondary antibody (Abcam, Cambridge, MA).…”

Section: Methodsmentioning

confidence: 99%

“…Defects in the insulin receptor signaling pathway represents a major target for modulating critical energy functions such as glucose and lipid metabolism, neuronal growth and survival, and synaptic plasticity (38–40). Recently, we showed that high plasma and CSF soluble insulin receptor (sIR) levels are associated with the presence and severity of HAND in a cohort of HIV-infected women on cART (41, 42). Moreover, we observed an increased binding of plasma insulin to sIR in patients with worse cognitive performance (42).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we showed that high plasma and CSF soluble insulin receptor (sIR) levels are associated with the presence and severity of HAND in a cohort of HIV-infected women on cART (41, 42). Moreover, we observed an increased binding of plasma insulin to sIR in patients with worse cognitive performance (42). Hence, there is a need to identify the factors that contribute to the secretion of sIR into the CSF.…”

Section: Introductionmentioning

confidence: 99%

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Release of Soluble Insulin Receptor From Neurons by Cerebrospinal Fluid From Patients With Neurocognitive Dysfunction and HIV Infection

et al. 2019

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Previously, we found that high levels of soluble insulin receptor (sIR) in the cerebrospinal fluid (CSF) of an HIV-infected women cohort were associated with the presence and severity of HIV-associated neurocognitive disorders (HAND). In this study we investigated if CSF from this population, HIV-1 Tat, and selected cytokines induces sIR secretion from human neuronal cells. Twenty-three (23) HIV-seropositive women stratified by cognitive status and five HIV- seronegative women were evaluated. Soluble IR levels were measured in the extracellular medium of neuronal cells (SH-SY5Y) that were exposed (for 24 h) to the CSF of patients. The levels of sIR, HIV-1 Tat, and cytokine levels (IL-2, IL4, IL-6, IFNγ, TNFα, and IL-10) were quantified in the CSF of participants by ELISA and flow cytometry. Neuronal secretion of sIR was measured after exposure (24 h) to HIV-1 Tat (0.5–250 nM), or specific cytokines. The effects of TNFα and HIV-1 Tat on sIR secretion were also evaluated in the presence of R7050 (TNFα antagonist; 10 nM). Neurons exposed to the CSF of HIV-infected women had higher sIR levels according to the severity of neurocognitive impairment of the participant. Increased CSF sIR levels were associated with the presence and severity of HAND and were positively correlated with CSF HIV-1 Tat levels in HIV-infected women with cognitive impairment. CSF levels of IL-2, IFNγ, and TNFα were significantly increased with HAND. However, only TNFα (5 pg/mL) and HIV-1 Tat (100 nM) induced a significant increase in neuronal sIR secretion after 24 h exposure, an effect that was antagonized when each were combined with R7050. Our data suggests that TNFα and HIV-1 Tat from the CSF of HIV-infected women may regulate the secretion of sIR from neuronal cells and that the effect of HIV-1 Tat on sIR secretion may depend on TNFα receptor activation.

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Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Release of Soluble Insulin Receptor From Neurons by Cerebrospinal Fluid From Patients With Neurocognitive Dysfunction and HIV Infection

et al. 2019

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“…[194][195][196] Currently, no HAND-specific therapies exist, but small trials of paroxetine and maraviroc showed some benefit in improving neurocognitive function in HIV+ cART-treated adults while trials of intranasal insulin are ongoing after in vitro evidence suggested insulin may have neuroprotective effects in HIV infection. [197][198][199][200][201] Development of validated biomarkers and improved clinical neurocognitive tests that can holistically and accurately assess the risk of developing HAND are also needed to facilitate future trials of novel HAND therapies. Table 6 includes a review of key biomarkers associated with HIVassociated cognitive impairment.…”

Section: Comorbid Conditionsmentioning

confidence: 99%

Global HIV neurology

Thakur

Boubour

Saylor

et al. 2019

Aids

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: Neurological conditions associated with HIV remain major contributors to morbidity and mortality and are increasingly recognized in the aging population on long-standing combination antiretroviral therapy (cART). Importantly, growing evidence shows that the CNS may serve as a reservoir for viral replication, which has major implications for HIV eradication strategies. Though there has been major progress in the last decade in our understanding of the pathogenesis, burden, and impact of neurological conditions associated with HIV infection, significant scientific gaps remain. In many resource-limited settings, ARVs considered second or third line in the United States, which carry substantial neurotoxicity, remain mainstays of treatment, and patients continue to present with severe immunosuppression and central nervous system (CNS) opportunistic infections. Despite this, increased global access to cART has coincided with an aging HIV+ population with cognitive sequelae, cerebrovascular disease, and peripheral neuropathy. Further neurological research in low-income and middle-income countries (LMICs) is needed to address the burden of neurological complications in HIV+ patients, particularly regarding CNS viral reservoirs and their effects on eradication.

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The delicate balance between neurotoxicity and neuroprotection in the context of HIV‐1 infection

Sénécal

Barat

Tremblay

2020

Glia

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Human immunodeficiency virus type-1 (HIV-1) causes a spectrum of neurological impairments, termed HIV-associated neurocognitive disorder (HAND), following the infiltration of infected cells into the brain. Even though the implementation of antiretroviral therapy reduced the systemic viral load, the prevalence of HAND remains unchanged and infected patients develop persisting neurological disturbances affecting their quality of life. As a result, HAND have gained importance in basic and clinical researches, warranting the need of developing new adjunctive treatments. Nonetheless, a better understanding of the molecular and cellular mechanisms remains necessary. Several studies consolidated their efforts into elucidating the neurotoxic signaling leading to HAND including the deleterious actions of HIV-1 viral proteins and inflammatory mediators. However, the scope of these studies is not sufficient to address all the complexity related to HAND development. Fewer studies focused on an altered neuroprotective capacity of the brain to respond to HIV-1 infection. Neurotrophic factors are endogenous polyproteins involved in neuronal survival, synaptic plasticity, and neurogenesis. Any defects in the processing or production of these crucial factors might compose a risk factor rendering the brain more vulnerable to neuronal damages. Due to their essential roles, they have been investigated for their diverse interplays with HIV-1 infection. In this review, we present a complete description of the neurotrophic factors involved in HAND. We discuss emerging concepts for their therapeutic applications and summarize the complex mechanisms that down-regulate their production in favor of a neurotoxic environment. For certain factors, we finally address opposing roles that rather lead to increased inflammation.

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Soluble insulin receptor as a source of insulin resistance and cognitive impairment in HIV-seropositive women

Cited by 11 publications

References 34 publications

Release of Soluble Insulin Receptor From Neurons by Cerebrospinal Fluid From Patients With Neurocognitive Dysfunction and HIV Infection

Release of Soluble Insulin Receptor From Neurons by Cerebrospinal Fluid From Patients With Neurocognitive Dysfunction and HIV Infection

Global HIV neurology

The delicate balance between neurotoxicity and neuroprotection in the context of HIV‐1 infection

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