Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice
dc.creator | Joshi, Chaitanya R. | |
dc.creator | Stacy, Satomi | |
dc.creator | Sumien, Nathalie | |
dc.creator | Ghorpade, Anuja | |
dc.creator | Borgmann, Kathleen | |
dc.creator.orcid | 0000-0002-0077-9873 (Sumien, Nathalie) | |
dc.creator.orcid | 0000-0003-0897-390X (Borgmann, Kathleen) | |
dc.date.accessioned | 2022-07-11T15:29:25Z | |
dc.date.available | 2022-07-11T15:29:25Z | |
dc.date.issued | 2020-12-15 | |
dc.description.abstract | Despite effective antiretroviral therapy (ART), mild forms of HIV-associated neurocognitive disorders (HAND) continue to afflict approximately half of all people living with HIV (PLWH). As PLWH age, HIV-associated inflammation perturbs the balance between brain matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs), likely contributing to neuropathogenesis. The MMP/TIMP balance is associated with cognition, learning, and memory, with TIMPs eliciting neuroprotective effects. Dysregulation of the MMP/TIMP balance was evident in the brains of PLWH where levels of TIMP-1, the inducible family member, were significantly lower than non-infected controls, and MMPs were elevated. Here, we evaluated the MMP/TIMP levels in the doxycycline (DOX)-induced glial fibrillary acidic protein promoter-driven HIV-1 transactivator of transcription (Tat) transgenic mouse model. The HIV-1 protein Tat is constitutively expressed by most infected cells, even during ART suppression of viral replication. Many studies have demonstrated indirect and direct mechanisms of short-term Tat-associated neurodegeneration, including gliosis, blood-brain barrier disruption, elevated inflammatory mediators and neurotoxicity. However, the effects of acute vs. prolonged exposure on Tat-induced dysregulation remain to be seen. This is especially relevant for TIMP-1 as expression was previously shown to be differentially regulated in human astrocytes during acute vs. chronic inflammation. In this context, acute Tat expression was induced with DOX intraperitoneal injections over 3 weeks, while DOX-containing diet was used to achieve long-term Tat expression over 6 months. First, a series of behavior tests evaluating arousal, ambulation, anxiety, and cognition was performed to examine impairments analogous to those observed in HAND. Next, gene expression of components of the MMP/TIMP axis and known HAND-relevant inflammatory mediators were assessed. Altered anxiety-like, motor and/or cognitive behaviors were observed in Tat-induced (iTat) mice. Gene expression of MMPs and TIMPs was altered depending on the duration of Tat expression, which was independent of the HIV-associated neuroinflammation typically implicated in MMP/TIMP regulation. Collectively, we infer that HIV-1 Tat-mediated dysregulation of MMP/TIMP axis and behavioral changes are dependent on duration of exposure. Further, prolonged Tat expression demonstrates a phenotype comparable to asymptomatic to mild HAND manifestation in patients. | |
dc.description.sponsorship | This work was supported by the National Institute of Neurological Disorders and Stroke award R01 NS048837 to AG and KB. | |
dc.identifier.citation | Joshi CR, Stacy S, Sumien N, Ghorpade A and Borgmann K (2020) Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice. Front. Neurol. 11:593188. doi: 10.3389/fneur.2020.593188 | |
dc.identifier.issn | 1664-2295 | |
dc.identifier.uri | https://hdl.handle.net/20.500.12503/31555 | |
dc.identifier.volume | 11 | |
dc.publisher | Frontiers Media S.A. | |
dc.relation.uri | https://doi.org/10.3389/fneur.2020.593188 | |
dc.rights.holder | Copyright © 2020 Joshi, Stacy, Sumien, Ghorpade and Borgmann. | |
dc.rights.license | Attribution 4.0 International (CC BY 4.0) | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.source | Frontiers in Neurology | |
dc.subject | HIV-associated neurocognitive disorders (HAND) | |
dc.subject | Timp1 | |
dc.subject | anxiety | |
dc.subject | iTat mice | |
dc.subject | locomotor activity | |
dc.subject | neuroinflammation | |
dc.subject | tissue inhibitor of metalloproteinases 1 | |
dc.title | Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice | |
dc.type | Article | |
dc.type.material | text |
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