ABSTRACT
The widespread use of combination antiretroviral therapy (cART) has resulted in significantly reduced deaths from HIV-1 associated complications and opportunistic infections. However, it is estimated that up to 50% of HIV-1 infected individuals still develop HIV-1 associated neurocognitive disorders (HAND). With no treatment currently available for patients, there is a critical need to identify therapeutic approaches that can treat this disorder. Evidence suggests that targeting Peroxisome Proliferator-Activated Receptor-gamma (PPARγ) can be anti-inflammatory in neurological disorders. Here we show that treatment with PPARγ agonists (rosiglitazone or pioglitazone) in primary cultures of mouse glial cells reversed EcoHIV-induced inflammatory genes (TNFα, IL-1ß, CCL2, CCL3, CXCL10) and indicator of oxidative stress (iNOS). Furthermore, in vivo, mice administered with EcoHIV through intracranial injection resulted in upregulation of inflammatory genes (TNFα, IL-1ß, IFNγ, CCL2, CCL3, CXCL10) and oxidative stress marker (iNOS) in the brain which was reversed through intraperitoneal administration of PPARγ agonists (rosiglitazone or pioglitazone). Finally, we demonstrated that treatment with these compounds in vivo reduced EcoHIV p24 protein burden in the brain. Our results suggest that treatment with PPARγ agonists are anti-inflammatory and antiviral in an in vivo model of EcoHIV infection. These drugs hold promise as potential candidates for HAND treatment in the future.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , HIV-1/drug effects , PPAR gamma/agonists , Pioglitazone/pharmacology , Rosiglitazone/pharmacology , Animals , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Brain/drug effects , Brain/metabolism , Cells, Cultured , Disease Models, Animal , HIV Core Protein p24/metabolism , HIV Infections/drug therapy , HIV Infections/pathology , HIV-1/genetics , HIV-1/physiology , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Male , Mice , Mice, Inbred C57BL , Neuroglia/cytology , Neuroglia/drug effects , Neuroglia/metabolism , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Oxidative Stress/drug effects , PPAR gamma/metabolism , Pioglitazone/therapeutic use , Rosiglitazone/therapeutic use , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Amyloids are fibrillar protein superstructures that are commonly associated with diseases in humans and with physiological functions in various organisms. The precise mechanisms of amyloid formation remain to be elucidated. Surprisingly, we discovered that a bacterial Escherichia coli chaperone-like ATPase, regulatory ATPase variant A (RavA), and specifically the LARA domain in RavA, forms amyloids under acidic conditions at elevated temperatures. RavA is involved in modulating the proper assembly of membrane respiratory complexes. LARA contains an N-terminal loop region followed by a ß-sandwich-like folded core. Several approaches, including nuclear magnetic resonance spectroscopy and molecular dynamics simulations, were used to determine the mechanism by which LARA switches to an amyloid state. These studies revealed that the folded core of LARA is amyloidogenic and is protected by its N-terminal loop. At low pH and high temperatures, the interaction of the N-terminal loop with the folded core is disrupted, leading to amyloid formation.
