TY - JOUR
T1 - Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice
AU - Joshi, Chaitanya R.
AU - Stacy, Satomi
AU - Sumien, Nathalie
AU - Ghorpade, Anuja
AU - Borgmann, Kathleen
N1 - Funding Information:
This work was supported by the National Institute of Neurological Disorders and Stroke award R01 NS048837 to AG and KB.
Publisher Copyright:
© Copyright © 2020 Joshi, Stacy, Sumien, Ghorpade and Borgmann.
PY - 2020/12/15
Y1 - 2020/12/15
N2 - 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.
AB - 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.
KW - HIV-associated neurocognitive disorders (HAND)
KW - TIMP1
KW - anxiety
KW - iTat mice
KW - locomotor activity
KW - neuroinflammation
KW - tissue inhibitor of metalloproteinases 1
UR - http://www.scopus.com/inward/record.url?scp=85098515967&partnerID=8YFLogxK
U2 - 10.3389/fneur.2020.593188
DO - 10.3389/fneur.2020.593188
M3 - Article
AN - SCOPUS:85098515967
SN - 1664-2295
VL - 11
JO - Frontiers in Neurology
JF - Frontiers in Neurology
M1 - 593188
ER -