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.
Highlights
During the antiretroviral therapy (ART) era, the brain remains a viral reservoir for HIV [1,2,3], and milder forms of HIV-associated neurocognitive disorders (HAND) affect nearly 18 million HIVinfected individuals lowering the quality of life [4,5,6,7]
Tat expression was higher in the left posterior (LP) brain region (p = 0.013 and p = 0.023, respectively), compared to right hemisphere (RH) and left anterior (LA) with the i.p. induction method, while prolonged food-based method did not show changes in Tat expression in different gross brain regions (Supplementary Figure 1C)
We depicted that gene expressions of [1] select inflammatory cytokines were unchanged, [2] matrix metalloproteinases (MMPs) were elevated, [3] tissue inhibitor of metalloproteinases (TIMPs) were altered depending on the duration of Tat exposure, subsequently impacting the brain MMP/TIMP balance
Summary
During the antiretroviral therapy (ART) era, the brain remains a viral reservoir for HIV [1,2,3], and milder forms of HIV-associated neurocognitive disorders (HAND) affect nearly 18 million HIVinfected individuals lowering the quality of life [4,5,6,7] Patients suffering from these milder forms of HAND exhibit difficulty with working memory, executive functioning, and speed of information processing [6]. Despite a mild or asymptomatic phenotype, complex underlying mechanisms are implicated in HAND pathogenesis These mechanisms include secretion of proinflammatory mediators from infected and affected cells, blood-brain barrier (BBB) compromise, reactive astrogliosis, excitotoxicity, and imbalance of matrix metalloproteinases (MMPs) – tissue inhibitor of metalloproteinases (TIMPs) axis [8,9,10]. These include both constitutively expressed (MMP-2 and TIMP-2) and inducible (MMP-9, TIMP-1) proteins following injury or inflammation
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