Neuroprotective microRNAs combat HIV associated neurocognitive disorder (HAND) pathogenesis
Abstract: HIV associated neurocognitive disorder (HAND) is one of the most severe HIV co-morbidities. During early stage of HIV-1 infection, virus crosses the blood - brain barrier (BBB) and enter central nervous system (CNS) through infiltrating periphery monocytes/macrophages. These infiltrating infected monocytes/macrophages then serve as the source of virus initiate secondary infection in resident monocytic cells and glial cells. During the establishment of infection, neurons are not directly infected by the virus. However, tremendous volume of pro-inflammatory cytokines and chemokines as well as viral particles are released by infected/ exposed immune and glial cells in local environment leading to the neuronal stress and apoptosis. Clinically, the severity of HAND can be divided into three stages: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV associated dementia (HAD). The successful coverage of highly active anti-retroviral therapies (HAART) have significantly lower the incidence of HAD and MND. However, the ANI remains as the most common co-morbidity of HIV-1 infection. Nearly more than half of individuals living with HIV-1 infection present with some degree of neuronal impairment. Currently, no treatment is available to prevent or treat HAND or ANI. Thus, devising a method to manage HAND helps to improve the quality of life in HIV-1 positive population, which is of great public health significance.
In this study, specific MicroRNAs (miRNAs) have are evaluated to control HAND pathogenesis. MicroRNAs are small non-coding RNAs which play an important role in all biological pathways including homeostasis of cellular interaction, cell proliferation and differentiation, and in CNS, regulate production of neurotoxic and neuroprotective factors. Previous studies in our laboratory have identify specific miRNAs that may have a neuro-protective role. This was based on the studies comparing miRNA profiles between HIV-1 seronegative and HIV-1 seropositive individuals with or without HAND. As a result, my project focus on understanding the ability of these candidate miRNAs to alter neuroinflammatory chemokines/cytokines production as well as HIV production in monocytes/macrophages. In order to test this hypothesis, miRNAs are transduced and expressed in monocytic cell line, THP-1, microglia and finally in primary monocytes derived macrophages (MDMs). Upon LPS stimulation, miR-20a and miR-106b miRNA transduced monocytes cell lines are able to significantly reduce TNF-α production while miR-let-7a significantly downregulates IL6 secretion, similar results were also observed in the presence of NL-YU2 infection. Microglia cell expressing miR-106b was found to inhibit both IL-6 and IL-8 secretion upon LPS stimulation and miR-20a was found to reduce IL-6 production upon TNF-α stimulation. Finally, miR-20a, miR-106b, miR-124 and let-7a were found to reduce HIV-1 viral reactivation in latent HIV-1 cell line, J-Lat, clone full length 10.6. These results indicate that neuroprotective miRNAs may have a role in reducing specific cytokines production and may affect the production of pro-inflammatory factors that resulting in viral reactivation. Thus, these miRNAs could have a potential therapeutics role to minimize neuroinflammatory cytokine induced neuronal death and thus manage HAND progression.
Advisor: Dr. Velpandi Ayyavoo