Understanding the Role of Astrocytes in HIV-1 Neuropathogenesis: Novel strategies to target astrocyte function and HIV-1 Associated Neurocognitive Disorder
HIV-1 infection is also associated with changes in cognition and neuronal function, known as HIV-associated neurocognitive disorder (HAND), with the most severe form resulting in dementia. Resident astrocytes in the frontal cortex have a critical role in neuropathogenesis induced by HIV-1 as they undergo “astrocytosis” that is commonly found in HAND subjects. Astrocytes are a type of glial cells located in the central nervous system and are targets for HIV-1 infection, though it is defective in producing replication competent viruses. However, the infected astrocytes are capable of producing viral proteins and are reactivated. These star-shaped cells serve many functions, such as providing structural support to nearby neurons and have a central role in maintenance of neuronal synapse. Astrocytes undergo structural and functional transformations in the occurrence of CNS infection, but it is unclear whether this plays a helpful or harmful role in HIV pathogenesis. Host cellular factors including microRNAs have been suggested to regulate the balance between neuroprotective and neurotoxic factors in astrocytes.
While ART can be used to treat viral replication, these drugs do not penetrate the central nervous system, and therefore treatment of infection within the brain is limited. Thus, identifying new therapeutics is important to reduce the burden of HAND. We have previously identified candidate miRNA that are known to have neuroprotective effects. In my project, I propose to evaluate whether these miRNA have a role in regulating virus replication and reactivation in astrocytes.
The primary goal of this study is to evaluate the role of microRNAs as therapeutics in virus replication in astrocytes.
Aim 1: To generate and characterize the astrocyte cell lines expressing candidate miRNAs along with appropriate control.
Aim 2: To determine whether the overexpression of these candidate miRNA block virus replication.