Expression of Human Immunodeficiency Virus Transactivator of Transcription (HIV-Tat1-86) Protein Alters Nociceptive Processing that is Sensitive to Anti-Oxidant and Anti-Inflammatory Interventions

Cirino, Thomas J.; Alleyne, Amy R.; Duarte, Vinicius; Figueroa, Ariana M; Simons, Chloe A.; Anceaume, Emet M.; Kendrick, Justin; Wallman, Olivia; Eans, Shainnel O.; Stacy, Heather M.; Medina, Jéssica; McLaughlin, Jay P.

doi:10.1007/s11481-021-09985-4

Cited by 11 publications

(7 citation statements)

References 58 publications

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“…In contrast, multiple studies demonstrated changes in endocannabinoid levels and related lipids following Tat exposure (Bosetti, 2007;Tallima and El Ridi, 2018;Hermes et al, 2021) as well as Tat-induced changes in CB 1 R, CB 2 R, and FAAH enzyme expression (Hauser et al, 2007;Wang et al, 2021). Alterations of the endocannabinoid system in postmortem tissue of PLWH has been demonstrated previously with reported changes in CB 1 R and CB 2 R expression in the frontal lobe (Chen et al, 2017;Duarte et al, 2021), as well as increases in FAAH expression in cortical postmortem tissue samples from rhesus monkeys infected with simian immunodeficiency virus displaying encephalitis (Rubin et al, 2019). The upregulation of AA levels in the striatum and cerebellum of Tat(+) male mice is not surprising as AA plays an important role in pro-and anti-inflammatory responses (Maki and Martin-Thormeyer, 2009;Maki et al, 2018;Sundermann et al, 2018), and chronic Tat and HIV-1 infection in the CNS increases inflammatory processes via upregulation of inflammatory mediators and glia activation (Ziegler and Altfeld, 2016;Ajasin and Eugenin, 2020;Santinelli et al, 2020).…”

Section: Discussionmentioning

confidence: 79%

“…Chronic pain is commonly reported by PLWH ( Ellis et al, 2009 ; Johnson et al, 2010 ) and significantly interferes with daily function ( Robinson-Papp et al, 2020 ). Preclinical studies using the Tat transgenic mouse model have reported mechanical allodynia, thermal hyperalgesia, and damage to nerve fibers due to Tat expression ( Chi et al, 2011 ; Wodarski et al, 2018 ; Cirino et al, 2021 ), but others have found either no effects ( Kronemer et al, 2017 ) or decreased pain sensitivity ( Bagdas et al, 2020 ). The current study supports the finding that Tat induction attenuates pain sensitivity but only at the supraspinal level without affecting the spinal-related tail flick task.…”

Section: Discussionmentioning

confidence: 99%

“…HIV Tat is secreted by infected cells ( Ensoli et al, 1990 ; Sabatier et al, 1991 ; Conant et al, 1994 ; King et al, 2006 ; Kannan et al, 2022 ) and can interact with cell surface receptors of uninfected neuronal and glial cells ( Philippon et al, 1994 ; Prendergast et al, 2002 ; Fitting et al, 2014 ), thus directly damaging neuronal structure and function ( Sabatier et al, 1991 ; Cheng et al, 1998 ; Bertrand et al, 2014 ; Hermes et al, 2021 ), as well as indirectly by promoting proinflammatory signaling via glial activation ( Nath et al, 1999 ; Hahn et al, 2010 ; Jin et al, 2012 ). Further, using the HIV Tat transgenic mouse model, various studies have demonstrated deficits in learning and memory, motivation, and motor activity ( Fitting et al, 2013 ; Kesby et al, 2016 ; Zhao et al, 2020 ; League et al, 2021 ), as well as Tat’s contribution to HIV-related neuropathic pain ( Chi et al, 2011 ; Wodarski et al, 2018 ; Bagdas et al, 2020 ; Cirino et al, 2021 ) and anxiety ( Paris et al, 2014 ; Hahn et al, 2016 ; Kasten et al, 2017 ; Joshi et al, 2020 ; Salahuddin et al, 2020 ; Qrareya et al, 2021 ), all of which recapitulate the pathological and behavioral abnormalities associated with HAND.…”

Section: Introductionmentioning

confidence: 99%

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Effects of acute cannabidiol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Yadav-Samudrala,

Gorman,

Barmada

et al. 2024

Front. Neurosci.

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BackgroundSome evidence suggests that cannabidiol (CBD) has potential to help alleviate HIV symptoms due to its antioxidant and anti-inflammatory properties. Here we examined acute CBD effects on various behaviors and the endocannabinoid system in HIV Tat transgenic mice.MethodsTat transgenic mice (female/male) were injected with CBD (3, 10, 30 mg/kg) and assessed for antinociception, activity, coordination, anxiety-like behavior, and recognition memory. Brains were taken to quantify endocannabinoids, cannabinoid receptors, and cannabinoid catabolic enzymes. Additionally, CBD and metabolite 7-hydroxy-CBD were quantified in the plasma and cortex.ResultsTat decreased supraspinal-related nociception and locomotion. CBD and sex had little to no effects on any of the behavioral measures. For the endocannabinoid system male sex was associated with elevated concentration of the proinflammatory metabolite arachidonic acid in various CNS regions, including the cerebellum that also showed higher FAAH expression levels for Tat(+) males. GPR55 expression levels in the striatum and cerebellum were higher for females compared to males. CBD metabolism was altered by sex and Tat expression.ConclusionFindings indicate that acute CBD effects are not altered by HIV Tat, and acute CBD has no to minimal effects on behavior and the endocannabinoid system.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of acute cannabidiol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Yadav-Samudrala,

Gorman,

Barmada

et al. 2024

Front. Neurosci.

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“…Note that in the current study Tat(+) mice did not show altered levels of pain sensitivity to heat-evoked spontaneous nociception with vehicle exposure. Neuropathic pain is commonly reported in PLWH(Lu et al, 2021;Slawek, 2021) and mouse models have demonstrated allodynia and damage to nerve bers resulting from induced Tat expression(Chi et al, 2011;Wodarski et al, 2018;Cirino et al, 2021…”

mentioning

confidence: 99%

Effects of acute Δ9 -tetrahydrocannabinol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Yadav-Samudrala

Gorman

Dodson

et al. 2022

Preprint

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Cannabis use is highly prevalent especially among people living with HIV (PLWH). Activation of the anti-inflammatory and neuroprotective endocannabinoid system by phytocannabinoids, i.e. Δ9-tetrahydrocannabinol (THC), has been proposed to reduce HIV symptoms. However, THC’s effects on HIV-associated cognitive impairments are unclear. Using HIV-1 Tat transgenic mice, the current study investigates acute THC effects on various behavioral outcomes and the endocannabinoid system. Minor or no effects of THC doses (1, 3, 10 mg/kg) were noted for body mass, body temperature, locomotor activity, and coordination, but spontaneous nociception was significantly decreased, with Tat induction increasing antinociceptive THC effects. Anxiogenic effects of THC (10 mg/kg) were demonstrated in Tat(−) females and males compared to vehicle-treated mice, with overall increased anxiety-like behavior in females compared to males. Object recognition memory was diminished by acute THC (10 mg/kg) injections in Tat(−) but not Tat(+) females, without affecting males. For the endocannabinoid system and related lipids, no effects were noted for acute THC, but female sex and Tat induction was associated with elevated 2-AG, AEA, AA, CB1R, CB2R, FAAH and/or MAGL expression in various CNS regions. Further, females demonstrated higher AEA levels compared to males in most CNS structures, and AEA levels in the prefrontal cortex of Tat(+) females were negatively associated with recognition memory. Overall, findings indicate that acute THC exposure exerts differential effects on behavior in the context of neuroHIV dependent on sex, potentially due to an altered endocannabinoid system, which may be of relevance in view of potential cannabis-based treatment options for PLWH.

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“…Although nestlet shredding did not correlate with PFC cytokine levels, Tat and morphine induce inflammation and neuronal dysfunction in the enteric nervous system [ 114 , 115 , 116 ], which may contribute to the reduced nesting behavior in the present study. Interestingly, previous research found no difference in nestlet shredding in Tat(+) mice in non-home test cages for 2 h [ 59 , 117 ], indicating timing and environmental factors also affect Tat-induced reductions in nest-building behavior. The morphine-induced decrease of burrowing was also exacerbated in Tat(+) mice, suggesting that Tat and morphine in combination are particularly detrimental to well-being.…”

Section: Discussionmentioning

confidence: 99%

Depressive-like Behavior Is Accompanied by Prefrontal Cortical Innate Immune Fatigue and Dendritic Spine Losses after HIV-1 Tat and Morphine Exposure

Nass

Hahn

Ohene‐Nyako

et al. 2023

Viruses

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Opioid use disorder (OUD) and HIV are comorbid epidemics that can increase depression. HIV and the viral protein Tat can directly induce neuronal injury within reward and emotionality brain circuitry, including the prefrontal cortex (PFC). Such damage involves both excitotoxic mechanisms and more indirect pathways through neuroinflammation, both of which can be worsened by opioid co-exposure. To assess whether excitotoxicity and/or neuroinflammation might drive depressive behaviors in persons infected with HIV (PWH) and those who use opioids, male mice were exposed to HIV-1 Tat for eight weeks, given escalating doses of morphine during the last two weeks, and assessed for depressive-like behavior. Tat expression decreased sucrose consumption and adaptability, whereas morphine administration increased chow consumption and exacerbated Tat-induced decreases in nesting and burrowing—activities associated with well-being. Across all treatment groups, depressive-like behavior correlated with increased proinflammatory cytokines in the PFC. Nevertheless, supporting the theory that innate immune responses adapt to chronic Tat exposure, most proinflammatory cytokines were unaffected by Tat or morphine. Further, Tat increased PFC levels of the anti-inflammatory cytokine IL-10, which were exacerbated by morphine administration. Tat, but not morphine, decreased dendritic spine density on layer V pyramidal neurons in the anterior cingulate. Together, our findings suggest that HIV-1 Tat and morphine differentially induce depressive-like behaviors associated with increased neuroinflammation, synaptic losses, and immune fatigue within the PFC.

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Expression of Human Immunodeficiency Virus Transactivator of Transcription (HIV-Tat1-86) Protein Alters Nociceptive Processing that is Sensitive to Anti-Oxidant and Anti-Inflammatory Interventions

Cited by 11 publications

References 58 publications

Effects of acute cannabidiol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Effects of acute cannabidiol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Effects of acute Δ9 -tetrahydrocannabinol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Depressive-like Behavior Is Accompanied by Prefrontal Cortical Innate Immune Fatigue and Dendritic Spine Losses after HIV-1 Tat and Morphine Exposure

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