Potential pharmacological approaches for the treatment of HIV-1 associated neurocognitive disorders.

HIV associated neurocognitive disorders (HAND) are the spectrum of cognitive impairments present in patients infected with human immunodeficiency virus type 1 (HIV-1). The number of patients affected with HAND ranges from 30 to 50% of HIV infected individuals and although the development of combinational antiretroviral therapy (cART) has improved longevity, HAND continues to pose a significant clinical problem as the current standard of care does not alleviate or prevent HAND symptoms. At present, the pathological mechanisms contributing to HAND remain unclear, but evidence suggests that it stems from neuronal injury due to chronic release of neurotoxins, chemokines, viral proteins, and proinflammatory cytokines secreted by HIV-1 activated microglia, macrophages and astrocytes in the central nervous system (CNS). Furthermore, the blood-brain barrier (BBB) not only serves as a route for HIV-1 entry into the brain but also prevents cART therapy from reaching HIV-1 brain reservoirs, and therefore could play an important role in HAND. The goal of this review is to discuss the current data on the epidemiology, pathology and research models of HAND as well as address the potential pharmacological treatment approaches that are being investigated.

Selective peroxisome proliferator-activated receptor-gamma modulator, INT131 exhibits anti-inflammatory effects in an EcoHIV mouse model.

Despite the use of antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments, that is, HIV-1-associated neurocognitive disorders remain prevalent potentially due to persistent viral replication, production of viral proteins, associated brain inflammation or in certain instances, antiretroviral neurotoxicity. Cellular targets in the brain include microglia which in response to infection release inflammatory markers and viral proteins. Evidence suggests that PPARγ agonists exert anti-inflammatory properties in neurological disorders. However, these agonists namely, thiazolidinediones have limited use in the clinic due to reported adverse side effects. INT131 is a novel non-thiazolidinedione compound that belongs to a new class of drugs known as selective PPARγ modulators. INT131 is considered to have a safer profile; however, its neuroprotective role in vivo is not known.The goal of this study was to examine the effect of INT131 in the context of EcoHIV-induced inflammation in vitro, in primary cultures of mouse glial cells and in vivo, in a mouse model of EcoHIV-associated brain inflammation, as well as characterize its pharmacokinetic properties and brain penetration. In primary cultures of glial cells and in the in vivo mouse model, EcoHIV exposure resulted in a significant elevation of inflammatory markers such as TNFα, IL-1ß, CCL3, and C3 which were attenuated with INT131 treatment. Pharmacokinetic analyses revealed that INT131 penetrates into the brain with a brain to blood partition ratio Kp value of 8.5%. Overall, this is the first report to demonstrate that INT131 could be a potential candidate for the treatment of HIV-1-associated brain inflammation.

Peroxisome Proliferator-Activated Receptor-gamma agonists exhibit anti-inflammatory and antiviral effects in an EcoHIV mouse model.

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.

Peroxisome proliferator-activated receptor-gamma: potential molecular therapeutic target for HIV-1-associated brain inflammation.

BACKGROUND: Despite the use of combination antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments remain prevalent due to persistent viral replication and associated brain inflammation. Primary cellular targets of HIV-1 in the brain are macrophages, microglia, and to a certain extent astrocytes which in response to infection release inflammatory markers, viral proteins [i.e., glycoprotein 120 (gp120)] and exhibit impaired glutamate uptake. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors. Compelling evidence suggests that PPARγ exerts anti-inflammatory properties in neurological disorders. The goal of this study was to examine the role of PPARγ in the context of HIV-1ADA gp120-induced inflammation in vitro, in primary cultures of rat astrocytes and microglia, and in vivo, in a rodent model of HIV-1ADA gp120-associated brain inflammation. METHODS: Primary mixed cultures of rat astrocytes and microglia were treated with PPARγ agonists (rosiglitazone or pioglitazone) and exposed to HIV-1ADA gp120. Inflammatory cytokines and indicator of oxidative stress response (TNFα, IL-1ß, iNOS) were measured using qPCR, and glutamate transporter (GLT-1) was quantified by immunoblotting. In vivo, rats were administered an intracerebroventricular injection of HIV-1ADA gp120 and an intraperitoneal injection of PPARγ agonist (rosiglitazone) or co-administration with PPARγ antagonist (GW9662). qPCR and immunoblotting analyses were applied to measure inflammatory markers, GLT-1 and PPARγ. RESULTS: In primary mixed cultures of rat astrocytes and microglia, HIV-1ADA gp120 exposure resulted in a significant elevation of inflammatory markers and a decrease in GLT-1 expression which were significantly attenuated with rosiglitazone or pioglitazone treatment. Similarly, in vivo, treatment with rosiglitazone reversed the gp120-mediated inflammatory response and downregulation of GLT-1. Furthermore, we demonstrated that the anti-inflammatory effects of PPARγ agonist rosiglitazone were mediated through inhibition of NF-κB. CONCLUSION: Our data demonstrate that gp120 can induce an inflammatory response and decrease expression of GLT-1 in the brain in vitro and in vivo. We have also successfully shown that these effects can be reversed by treatment with PPARγ agonists, rosiglitazone or pioglitazone. Together our data suggest that targeting PPARγ signaling may provide an option for preventing/treating HIV-associated brain inflammation.

Role and modulation of drug transporters in HIV-1 therapy.

Current treatment of human immunodeficiency virus type-1 (HIV-1) infection involves a combination of antiretroviral drugs (ARVs) that target different stages of the HIV-1 life cycle. This strategy is commonly referred to as highly active antiretroviral therapy (HAART) or combined antiretroviral therapy (cART). Membrane-associated drug transporters expressed ubiquitously in mammalian systems play a crucial role in modulating ARV disposition during HIV-1 infection. Members of the ATP-binding cassette (ABC) and solute carrier (SLC) transporter superfamilies have been shown to interact with ARVs, including those that are used as part of first-line treatment regimens. As a result, the functional expression of drug transporters can influence the distribution of ARVs at specific sites of infection. In addition, pathological factors related to HIV-1 infection and/or ARV therapy itself can alter transporter expression and activity, thus further contributing to changes in ARV disposition and the effectiveness of HAART. This review summarizes current knowledge on the role of drug transporters in regulating ARV transport in the context of HIV-1 infection.