Velpandi Ayyavoo

HIV-1 associated Neuropathogenesis: Role of Neurogranin: HIV-1 associated neurocognitive disorders (HAND) is observed in more than 60% of HIV-1 positive patients despite effective viral suppression through combined antiretroviral therapy (cART). HIV-1 enters into the brain during early infection via infected monocytes/macrophages and microglia and establishes chronic infection in the CNS compartment. Whereas, neurons are not directly infected by HIV-1, yet these are the most affected cells in the CNS compartment. Chronic neuroinflammation combined with the presence of viral and host cellular factors contribute to astrogliosis and neurodegenerative changes observed in the brain of HIV-1 subjects. Our laboratory has shown a significant loss in the level of Neurogranin (Nrgn), a synaptic dendritic protein in the brain of HIV-infected individuals with HAND. Because of its central role in calcium signaling and synaptic plasticity, the loss of Nrgn expression may contribute significantly to LTP inhibition, memory loss and cognitive dysfunction in individuals with HAND. Thus, there is a strong premise to evaluate the contribution of Nrgn in HAND. We hypothesize that loss of neuronal Neurogranin (Nrgn) has a critical role in HAND pathogenesis, contributing to cognitive dysfunction. Research projects in the laboratory are currently geared towards addressing the role of Nrgn in HAND pathogenesis.

Development of 3D CNS organoid model to study neurodegenerative diseases: Studying neurodegenerative diseases is complex and quite fascinating. Understanding how HIV-1 affects the brain and results in the development of HAND is the major focus of our laboratory. However, it is rather difficult due to the inability to obtain primary tissues or cells (neurons, astrocytes) from patients. One of the approaches is the use of 3D organoids that is very relevant to the physiological conditions and cell lineages observed in the brain. In an effort to develop such an organoid model, we propose to use three cell types (microglia, neurons, and astrocytes) that are known to play a critical role in HIV CNS infection and pathology. These cells will be derived from neuronal progenitor cells (NPCs) by various differentiation methodologies that will mimic the adult brain (see figure below showing primary Neurons and Astrocytes developed from NPCs). Studies are in progress to develop 3D culture and to further understand how HIV-1 alters the function, viability, and synaptic communication.

MicroRNAs as therapeutics targeting Neuroinflammation: HIV-1 infected macrophages survive for a long time in the central nervous system (CNS) and these cells likely mediate neuropathological changes observed in HIV subjects. However, there are no effective therapeutics to target the virus in the CNS compartment is available, thus there is an unmet need to develop agents that could potentially block and/or reverse chronic neuroinflammation and the associated pathologies in CNS of HIV-1 subjects with cART. Loss of higher mental functions lowers the quality of life of those who suffer and imposes a tremendous financial burden on society in the form of health care costs, disability and lost productivity. Using omics approaches, we have identified that a unique subset of HIV-1 subjects (HAND resistant subjects) express specific miRNAs as key regulators of neuroinflammation and disease progression compared to HIV-1 subjects with HAND. Based on these findings, we hypothesize that chronic inflammation associated with persistence of HIV-1 infected macrophages in the CNS is a major contributing factor to HAND development in the presence of cART. Thus, skewing the proinflammatory glial microenvironment to anti-inflammatory and neuroprotective micro-environment will be beneficial to the host. We propose to develop novel immunomodulatory agents to target persistent HIV-1 infection and associated chronic inflammation in the CNS.