HIV-1 Tat and opioids act independently to limit antiretroviral brain concentrations and reduce blood–brain barrier integrity

Leibrand, Crystal R.; Paris, Jason J.; Jones, Adam G.; Masuda, Quamrun N.; Halquist, Matthew S.; Kim, Woong‐Ki; Knapp, Pamela E.; Kashuba, Angela D. M.; Hauser, Kurt F.; McRae, MaryPeace

doi:10.1007/s13365-019-00757-8

Cited by 29 publications

(27 citation statements)

References 127 publications

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“…Regional differences in cytokine levels differ with age, onset of insult, and duration ( Deverman and Patterson, 2009 ; Drabek et al, 2015 ). The Tat-induced changes in cytokines were regionally specific, which agrees with previous in vitro findings in astrocyte-enriched cultures ( Fitting et al, 2010b ), and may reflect glial heterogeneity or regional alterations in blood-brain barrier integrity ( Leibrand et al, 2017 , 2019 ). Tat induction in the PFC increased expression of proinflammatory cytokines (i.e., IL-12p40), chemokines (i.e., CCL4, CXCL1, and G-CSF), and anti-inflammatory cytokines (i.e., IL-4 and IL-10).…”

Section: Discussionsupporting

confidence: 89%

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

Nass

Hahn

McLane

et al. 2020

Brain, Behavior, & Immunity - Health

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HIV-1 selectively disrupts neuronal integrity within specific brain regions, reflecting differences in viral tropism and/or the regional differences in the vulnerability of distinct neuronal subpopulations within the CNS. Deficits in prefrontal cortex (PFC)-mediated executive function and the resultant loss of behavioral control are a particularly debilitating consequence of neuroHIV. To explore how HIV-1 disrupts executive function, we investigated the effects of 48 h, 2 and/or 8 weeks of HIV-1 Tat exposure on behavioral control, synaptic connectivity, and neuroimmune function in the anterior cingulate cortex (ACC) and associated cortico-basal ganglia (BG)-thalamocortical circuitry in adult, Tat transgenic male mice. HIV-1 Tat exposure increased novelty-exploration in response to novel food, flavor, and environmental stimuli, suggesting that Tat triggers increased novelty-exploration in situations of competing motivation (e.g., drive to feed or explore vs. fear of novel, brightly lit open areas). Furthermore, Tat induced adaptability in response to an environmental stressor and pre-attentive filtering deficits. The behavioral insufficiencies coincided with decreases in the inhibitory pre- and post-synaptic proteins, synaptotagmin 2 and gephyrin, respectively, in the ACC, and alterations in specific pro- and anti-inflammatory cytokines out of 23 assayed. The interaction of Tat exposure and the resultant time-dependent, selective alterations in CCL4, CXCL1, IL-12p40, and IL-17A levels in the PFC predicted significant decreases in adaptability. Tat decreased dendritic spine density and cortical VGLUT1 inputs, while increasing IL-1β, IL-6, CCL5, and CCL11 in the striatum. Alternatively, IL-1α, CCL5, and IL-13 were decreased in the mediodorsal thalamus despite the absence of synaptic changes. Thus, HIV-1 Tat appears to uniquely and systematically disrupt immune regulation and the inhibitory and excitatory synaptic balance throughout the ACC-BG-thalamocortical circuitry resulting in a loss of behavioral control.

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Section: Discussionsupporting

confidence: 89%

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

Nass

Hahn

McLane

et al. 2020

Brain, Behavior, & Immunity - Health

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“…Similarly, rats self-administrating heroin [ 59 ] and mice undergoing heroin withdrawal [ 60 ] showed elevated levels of phenylalanine in serum. The lack of elevated phenylalanine concentrations in the spinal cord suggests regional differences in its metabolism (similar to tyrosine), which may coincide with regional differences in morphine concentration in the CNS [ 40 ]. Interestingly, Tat induction appeared to negate morphine-dependent increases in striatal phenylalanine in our study and Tat and/or HIV exposure have been associated with pathophysiological alterations in dopamine [ 115 – 118 ].…”

Section: Discussionmentioning

confidence: 99%

“…Since the inception of cART, the impact of chronic inflammatory insult by HIV-1 infection has become an important topic; persistent latently and productively infected perivascular macrophage and microglial populations [ 14 , 17 – 19 ] represent the primary reservoirs for HIV-1 in the CNS [ 20 – 24 ]. In vivo and in vitro studies focusing on the HIV-1 transactivator of transcription (Tat) protein demonstrate morphine’s exacerbating effects on microglial activation [ 25 – 29 ], astroglia dysregulation [ 29 – 32 ], cytokine production [ 33 – 38 ], and blood-brain barrier (BBB) breakdown [ 13 , 39 , 40 ], with additional effects on oxidative stress [ 33 , 34 , 41 , 42 ], intracellular calcium [ 34 , 37 , 43 ], and neurotoxicity [ 38 , 42 – 44 ], potentially due to morphine’s action on μ-opioid receptor (MOR)-expressing glia [ 31 , 45 ]. Notably, HIV-1 and HIV-1 proteins, such as Tat, impact opioid gene expression and splicing specificity [ 38 , 46 – 48 ], potentially mediated through the release of various proinflammatory cytokines, including IL-6, TNF, GM-CSF, and IFN-γ [ 49 , 50 ].…”

Section: Introductionmentioning

confidence: 99%

Escalating morphine dosing in HIV-1 Tat transgenic mice with sustained Tat exposure reveals an allostatic shift in neuroinflammatory regulation accompanied by increased neuroprotective non-endocannabinoid lipid signaling molecules and amino acids

Hermes

Jacobs

Key

et al. 2020

J Neuroinflammation

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Background Human immunodeficiency virus type-1 (HIV-1) and opiates cause long-term inflammatory insult to the central nervous system (CNS) and worsen disease progression and HIV-1-related neuropathology. The combination of these proinflammatory factors reflects a devastating problem as opioids have high abuse liability and continue to be prescribed for certain patients experiencing HIV-1-related pain. Methods Here, we examined the impact of chronic (3-month) HIV-1 transactivator of transcription (Tat) exposure to short-term (8-day), escalating morphine in HIV-1 Tat transgenic mice that express the HIV-1 Tat protein in a GFAP promoter-regulated, doxycycline (DOX)-inducible manner. In addition to assessing morphine-induced tolerance in nociceptive responses organized at spinal (i.e., tail-flick) and supraspinal (i.e., hot-plate) levels, we evaluated neuroinflammation via positron emission tomography (PET) imaging using the [18F]-PBR111 ligand, immunohistochemistry, and cytokine analyses. Further, we examined endocannabinoid (eCB) levels, related non-eCB lipids, and amino acids via mass spectrometry. Results Tat-expressing [Tat(+)] transgenic mice displayed antinociceptive tolerance in the tail withdrawal and hot-plate assays compared to control mice lacking Tat [Tat(−)]. This tolerance was accompanied by morphine-dependent increases in Iba-1 ± 3-nitrotryosine immunoreactive microglia, and alterations in pro- and anti-inflammatory cytokines, and chemokines in the spinal cord and striatum, while increases in neuroinflammation were absent by PET imaging of [18F]-PBR111 uptake. Tat and morphine exposure differentially affected eCB levels, non-eCB lipids, and specific amino acids in a region-dependent manner. In the striatum, non-eCB lipids were significantly increased by short-term, escalating morphine exposure, including peroxisome proliferator activator receptor alpha (PPAR-α) ligands N-oleoyl ethanolamide (OEA) and N-palmitoyl ethanolamide (PEA), as well as the amino acids phenylalanine and proline. In the spinal cord, Tat exposure increased amino acids leucine and valine, while morphine decreased levels of tyrosine and valine but did not affect eCBs or non-eCB lipids. Conclusion Overall results demonstrate that 3 months of Tat exposure increased morphine tolerance and potentially innate immune tolerance evidenced by reductions in specific cytokines (e.g., IL-1α, IL-12p40) and microglial reactivity. In contrast, short-term, escalating morphine exposure acted as a secondary stressor revealing an allostatic shift in CNS baseline inflammatory responsiveness from sustained Tat exposure.

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“…We are not aware of any studies which deal with the capacity of the combination of tobacco smoke and chronic morphine to modulate inflammation. However, both of these insults may be related to their ability to impair the integrity of the blood–brain barrier 57 – 59 . Our results are consistent with the notion that the combination of these two insults provides a potent neuroinflammatory stimulus, leading to neuro-cognitive decline in HIV-infected patients who are smokers 60 .…”

Section: Discussionmentioning

confidence: 99%

Tobacco smoke and morphine alter peripheral and CNS inflammation following HIV infection in a humanized mouse model

Cornwell

Sriram

Seliga

et al. 2020

Sci Rep

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Tobacco smoking is common in HIV-infected patients, and is prevalent among intravenous opiate abusers. Conversely, intravenous opiate abusers are more likely HIV-infected, and opiate abuse is associated with more severe neuroinflammation. Given the coincident use of tobacco smoking among HIV-infected intravenous drug users (IVDUs), we set out to study the effects of smoke exposure, chronic morphine administration, and HIV infection using the NSG humanized mouse model. Our results show that smoke, morphine, and the combination promotes the decline in CD4 + t cells in HIV-infected mice. Further, chronic morphine administration increases the numbers of circulating CD8 + T cells which express the inhibitory receptor PD-1, as well as the cytolytic proteins perforin and granzyme B in the infected mice. We also found that the combination of smoke and morphine inhibited the expression of IL-1α, IL-4 and IL-17A. Finally, the combination of smoke and morphine exposure induces microglial activation following infection, as well as in the absence of HIV infection. To our knowledge, this is the first report to assess the combined effects of smoke and chronic morphine exposure on the inflammation associated with HIV infection, and demonstrate that these two insults exert significant neuroinflammatory activity. Tobacco smoking increases risks for multiple causes of illness and death 1. Approximately 20% of adults in the United States are cigarette smokers, and smoking is the leading cause of preventable mortality and morbidity, resulting in more than 425,000 deaths annually 2. People who use illicit drugs are known to have high rates of cigarette smoking. In a 24-year follow-up of narcotics addicts who were admitted to drug treatment, the death rates of smokers were four times that of non-smokers 3. Current estimates suggest that 75% of human immunodeficiency virus (HIV)-infected individuals smoke tobacco 4,5. Opiate drug abuse is a major contributing factor to the global acquired immune deficiency syndrome (AIDS) epidemic, and it is likely that over a third of HIV infections in the US can be linked to intravenous drug abuse, and global estimates suggest that almost 20% of intravenous drug abusers are infected with HIV 6-8. Among individuals living with HIV, studies have found that smokers are at greater risk than nonsmokers to develop bacterial pneumonia, oral lesions and AIDS dementia complex 9. This was particularly apparent in the era prior to the use of antiretroviral therapy 10. A recent study reported by Khanna et al. 11 has shown that tobacco smoke administration to rats results in substantial inflammation within the CNS. This response includes an upregulation of several cytokines including TNF-α, IL-17, TGF-β, and CCL2. The latter results support the notion that smoke induces inflammatory responses in the brain, consistent with the observation that the risk for HIV-associated neurodegeneration is greater in smokers, compared to non-smokers 9 .

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HIV-1 Tat and opioids act independently to limit antiretroviral brain concentrations and reduce blood–brain barrier integrity

Cited by 29 publications

References 127 publications

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

Escalating morphine dosing in HIV-1 Tat transgenic mice with sustained Tat exposure reveals an allostatic shift in neuroinflammatory regulation accompanied by increased neuroprotective non-endocannabinoid lipid signaling molecules and amino acids

Tobacco smoke and morphine alter peripheral and CNS inflammation following HIV infection in a humanized mouse model

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