Despite effective combination antiretroviral therapy (cART), virus persists in brain at low levels often in a latent or restricted manner. Immune activation and inflammation continues and is linked to viral and cellular neurotoxic proteins and co-morbid infections along with drugs of abuse. The severity of inflammation that occurs during cART is well known to be worsened by methamphetamine (Meth). The mechanisms that underlie such disease outcomes remain poorly understood. Complicating the ability to decipher mechanisms is that antiretroviral drugs (ARVs) may themselves affect inflammatory responses and elicit neurotoxicity during long- term usage. Thus, HIV, drugs of abuse and ARVs are believed to orchestrate changes in the brain?s microenvironment leading to microglia (MG) activation and consequent inflammatory activities. These, over time, affect the development of HIV-associated neurocognitive disorders (HAND). To date, there is considerable interest in strategies that regulate MG activation and resultant inflammation. Thus, investigations on development of specific biomarkers to judge the severity of inflammation and identification of specific targets to control MG activation and inflammation are of immediate importance. MG express outward delayed rectifier Kv1.3, with a direct tie into functional marker of MG activation and NLRP3 inflammasome is involved in HIV-induced MG activation. However, there is very limited information available on how Kv1.3 can be ?best? utilized as a biomarker for Meth potentiation of HIV-associated MG NLRP3 inflammasome activation. To this end, we seek funds to develop Kv1.3 as a potential biomarker and to evaluate its potential as an intersecting target for HIV, Meth and ARVs in laboratory and animal models.
In specific aim 1, we will determine and characterize the role of Kv1.3 in Meth- and ARV-induced potentiation of MG activation, migration, production of neurotoxins and neurotoxic activity via NLRP3 activation.
In specific aim 2, we will investigate the relationships between Kv1.3-associated MG NLRP3 activation and HIV-associated neuronal injury and behavioral deficits in infected humanized mice. We theorize that Kv1.3 channels can be harnessed as physiological biomarkers for inflammation and neurotoxicity seen during HAND. This rests in the fact that such channels closely regulate MG activation, migration and production of pro-inflammatory substances. Overall, these studies, if successful, may have the potential to develop a biomarker for judging the severity of HIV-, Meth- and ARV-associated neuroinflammation and to identify a potential intersecting target for the development of therapeutic strategies.
This grant proposal investigates how drug abuse, in particular methamphetamine (Meth), potentiates HIV- induced microglia NLRP3 inflammasome activation and inflammation in the era of combined antiretroviral therapy (cART). It will focus on the role played by voltage-gated potassium channel Kv1.3 in modulating microglia NLRP3 inflammasome activation and inflammatory responses induced by HIV, Meth and antiretroviral drugs alone or in combination. The proposed studies may uncover an intersecting target for the three and may lead to development of a potential biomarker for judging microglial NLRP3 inflammasome activation and resultant inflammation. The outcomes of the proposed studies may have translational potential.
