Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice

Paris, Jason J.; Singh, Harminder D.; Carey, Amanda N.; McLaughlin, Jay P.

doi:10.1016/j.bbr.2015.05.021

Cited by 49 publications

(47 citation statements)

References 53 publications

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“…This notion is in consistence with previous studies that virus, Tat and gp120 may directly contribute to HAND (Paris et al 2015;Podhaizer et al 2012;Zou et al 2007). Because gp120 glycoproteins can be taken up by brain microvessels and transported across the BBB (Banks et al 2005), it is possible that higher brain P24 antgenemia in HIV-1 JR-FL -infected mice contribute to severer neuron damages as compared with HIV-1 BJZS7 -infected animals.…”

Section: Discussionsupporting

confidence: 53%

Brain Invasion by CD4+ T Cells Infected with a Transmitted/Founder HIV-1BJZS7 During Acute Stage in Humanized Mice

Liu

Cheung

et al. 2016

J Neuroimmune Pharmacol

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Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is one of the common causes of cognitive dysfunction and morbidity among infected patients. However, to date, it remains unknown if a transmitted/founder (T/F) HIV-1 leads to neurological disorders during acute phase of infection. Since it is impossible to answer this question in humans, we studied NOD.Cg-Prkdc scid Il2rgtm1Wjl/SzJ mice (NSG) reconstituted with human PBMC (NSG-HuPBL), followed by the peritoneal challenge with the chronic HIV-1JR-FL and the T/F HIV-1BJZS7, respectively. By measuring viral load, P24 antigenemia and P24(+) cells in peripheral blood and various tissue compartments, we found that systemic infections were rapidly established in NSG-HuPBL mice by both HIV-1 strains. Although comparable peripheral viral loads were detected during acute infection, the T/F virus appeared to cause less CD4(+) T cell loss and less numbers of infected cells in different organs and tissue compartments. Both viruses, however, invaded brains with P24(+)/CD3(+) T cells detected primarily in meninges, cerebral cortex and perivascular areas. Critically, brain infections with HIV-1JR-FL but not with HIV-1BJZS7 resulted in damaged neurons together with activated microgliosis and astrocytosis as determined by significantly increased numbers of Iba1(+) microglial cells and GFAP(+) astrocytes, respectively. The increased Iba1(+) microglia was correlated positively with levels of P24 antigenemia and negatively with numbers of NeuN(+) neurons in brains of infected animals. Our findings, therefore, indicate the establishment of two useful NSG-HuPBL models, which may facilitate future investigation of mechanisms underlying HIV-1-induced microgliosis and astrocytosis.

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Section: Discussionsupporting

confidence: 53%

Brain Invasion by CD4+ T Cells Infected with a Transmitted/Founder HIV-1BJZS7 During Acute Stage in Humanized Mice

Liu

Cheung

et al. 2016

J Neuroimmune Pharmacol

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“…Additionally microglial cell induction of inflammosomes (innate immune response protein complexes that respond to pathogen associated molecular patterns) is precipitated during acute lentiviral infection, and inflammosome activation associates with brain pathology in a feline immunodeficiency model of HIV encephalitis [52]. Finally, HIV-Tat protein may be a direct trigger or in a pathway associated with processes leading to microglial activation, though the extent to which this is an important cause of ongoing activation in latent cART treated infection is unclear [53, 54]. Overall, this new understanding of the homeostasis and behavior of microglia supports their major role in contributing to the problem of persistent CNS immune activation in HIV: microglia respond to acute HIV in an immediate and dynamic fashion, and once perturbed they are resident cells of the CNS that may harbor integrated HIV long-term, associated with constant cellular immune activation.…”

Section: Immune Cells and Tissues Involved In Pathogenesismentioning

confidence: 99%

Immune activation in the central nervous system throughout the course of HIV infection

Spudich

2016

Current Opinion in HIV and AIDS

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Purpose of review Robust and dynamic innate and adaptive responses characterize the acute central nervous system (CNS) response to HIV and other viral infections. In a state of chronic infection or viral latency, persistent immune activation associates with pathology in the CNS. Understanding this process is critical, since immune-mediated pathology in non-renewable CNS cells may result in long-term neurologic sequelae for HIV infected individuals. Recent findings In humans, immune activation is reduced by suppressive combination antiretroviral therapy (cART), but persists at abnormally elevated levels on treatment. CNS immune activation is initiated in acute infection and progressively increases until cART is started. Newly identified characteristics of the CNS immune surveillance network include features of homeostasis and function of brain microglial cells, lymphatic drainage from CNS to cervical lymph nodes, and cells in cerebrospinal fluid associated with neurocognitive impairment. Summary More research is required to determine whether early intervention to reduce infection limits the immunopathology established by sustained immune responses that ultimately fail to resolve infection, and to unravel mechanisms of persistent immune activation during treated HIV so that strategies can be developed to therapeutically protect the brain.

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“…URB602, JZL184, AM5206) produce neuroprotective effects both in vitro (Chen et al, 2011; Naidoo et al, 2011) and in vivo (Lara-Celador et al, 2012; Naidoo et al, 2011), but their effects in models of neuro-acquired immune deficiency syndrome (neuroAIDS) are little explored. The HIV-1 protein transactivator of transcription (Tat) likely contributes to synaptodendritic injury observed in brains of HIV-1 infected individuals (Jones et al, 2000; Valle et al, 2000) and has been shown to cause dendritic structural and functional defects in vitro (Bertrand et al, 2013; Bertrand et al, 2014; Fitting et al, 2014; Haughey et al, 1999; Haughey et al, 2001; Kruman et al, 1998) and in vivo (Carey et al, 2012; Fitting et al, 2013; Fitting et al, 2010; Hahn et al, 2013; Paris et al, 2015). Tat activates both glutamatergic NMDA receptors (GluNs) (Aksenov et al, 2012; Fitting et al, 2014; Haughey et al, 2001; Li et al, 2008; Magnuson et al, 1995; Perez et al, 2001) and AMPA receptors (GluRs) (Longordo et al, 2006), leading to increased excitability (Brailoiu et al, 2008; Fitting et al, 2015; Ngwainmbi et al, 2014) as well as increases in [Na + ] i , mitochondrial instability, and excessive Ca 2+ influx (Fitting et al, 2014; Yu and Salter, 1998), all of which eventually cause dendritic swellings (Bertrand et al, 2014; Fitting et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Endocannabinoids exert CB 1 receptor-mediated neuroprotective effects in models of neuronal damage induced by HIV-1 Tat protein

Hermes

Nwanguma

et al. 2017

Molecular and Cellular Neuroscience

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In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is considered a chronic disease that specifically targets the brain and causes HIV-1-associated neurocognitive disorders (HAND). Endocannabinoids (eCBs) elicit neuroprotective and anti-inflammatory actions in several central nervous system (CNS) disease models, but their effects in HAND remain unknown. HIV-1 does not infect neurons, but produces viral toxins, such as transactivator of transcription (Tat), that disrupt neuronal calcium equilibrium and give rise to synaptodendritic injuries and cell death, the former being highly correlated with HAND. Consequently, we tested whether the eCBs N-arachidonoyl ethanolamine (anandamide/AEA) and 2-arachidonoyl-glycerol (2-AG) offer neuroprotective actions in a neuronal culture model. Specifically, we examined the neuroprotective actions of these eCBs on Tat excitotoxicity in primary cultures of prefrontal cortex neurons (PFC), and whether cannabinoid receptors mediate this neuroprotection. Tat-induced excitotoxicity was reflected by increased intracellular calcium levels, synaptodendritic damage, neuronal excitability, and neuronal death. Further, upregulation of cannabinoid 1 receptor (CB1R) protein levels was noted in the presence of HIV-1 Tat. The direct application of AEA and 2-AG reduced excitotoxic levels of intracellular calcium and promoted neuronal survival following Tat exposure, which was prevented by the CB1R antagonist rimonabant, but not by the CB2R antagonist AM630. Overall, our findings indicate that eCBs protect PFC neurons from Tat excitotoxicity in vitro via a CB1R-related mechanism. Thus, the eCB system possesses promising targets for treatment of neurodegenerative disorders associated with HIV-1 infection.

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Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice

Cited by 49 publications

References 53 publications

Brain Invasion by CD4+ T Cells Infected with a Transmitted/Founder HIV-1BJZS7 During Acute Stage in Humanized Mice

Brain Invasion by CD4+ T Cells Infected with a Transmitted/Founder HIV-1BJZS7 During Acute Stage in Humanized Mice

Immune activation in the central nervous system throughout the course of HIV infection

Endocannabinoids exert CB 1 receptor-mediated neuroprotective effects in models of neuronal damage induced by HIV-1 Tat protein

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