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-1β, 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-1β, 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.
Highlights
HIV-1 infection has been a prominent target for investigation and treatment, and many successful advances over the last two decades have greatly improved patient outcomes for those infected with the virus
Previous studies from our laboratory have shown that exposure to Peroxisome proliferator-activated receptor-γ (PPARγ) agonists reversed HIV-1 gp[120] induced mRNA expression of pro-inflammatory cytokines and oxidative stress markers in primary cultures of mixed rat astrocytes and microglia[28]
To confirm that the anti-inflammatory effects of PPARγ agonists rosiglitazone and pioglitazone were PPARγ dependent, cells were co-treated with the PPARγ specific antagonist, GW9662
Summary
HIV-1 infection has been a prominent target for investigation and treatment, and many successful advances over the last two decades have greatly improved patient outcomes for those infected with the virus. Other groups have used this model to investigate efficacy of ARVs16,20 and neuroprotective compounds[21] This established mouse model of HIV-1 neuropathogenesis was selected for our studies to investigate the effect of potential anti-inflammatory compounds in the context of HIV-1 associated brain inflammation and infection. Pioglitazone appears to hold promise for the treatment of HIV-1 associated lipodystrophy syndrome (HALS)[30,31] and hepatic steatosis in HIV/HCV patients[32] This agonist appears to be a safer PPARγ ligand with lesser cardiovascular side effects, even demonstrating reduced incidence of stroke in patients with type 2 diabetes[33] and merits further investigation as a possible treatment for HAND. These studies are promising, it not known whether pioglitazone treatment will lead to similar outcomes
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