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.
1991 | Madurai Kamaraj University, India | Doctor of Philosophy
1991-1993 | The Wistar Institute | Postdoctoral Fellow
1994-1998 | The University of Pennsylvania | Research Associate
IDM 2001 - Molecular Biology of Microbiol Pathogens
IDM 2023 - Laboratory Methods
IDM 2025 - Seminar Series & Journal Club
IDM 2010 - Pathogen Biology
IDM 2014 - Functional Genomics
Venkatachari NJ, Walker LA, Tastan O, Le T, Dempsey TM, Li Y, Yanamala N, Srinivasan A, Klein-Seetharaman J, Montelaro RC,Ayyavoo V. (2010) Human immunodeficiency virus type 1 Vpr: oligomerization is an essential feature for its incorporation into virus particles. Virology J. 7:119.
Guha D, Nagilla P, Redinger C, Srinivasan A, Schatten GAyyavoo V.(2012) Neuronal apoptosis by HIV-1 Vpr: Contribution of pro-inflammatory molecular networks from infected target cells. J Neuroinflammation 9:138-152.
Duskova K, Nagilla P, Le H, Iyer P, Thalamuthu A, Martinson J, Bar-Joseph Z, Buchanan W, Rinaldo C,Ayyavoo V. (2013) MicroRNA regulation and its effects on cellular transcriptome in Human Immunodeficiency Virus-1 (type-1) infected individuals with distinct viral load and CD4 cells. BMC Genomics 13:250.
Zych C, Domling A,Ayyavoo V. (2013) Development of a robust cell- based high-throughput screening assay to identify targets of HIV-1 Vpr dimerization. J. Drug Design Develop. Therapy 7:403-412.
Hadi K, Walker LA, Tarwater P, Srinivasan A,Ayyavoo V. (2014) Human Immunodeficiency Virus- type 1 (HIV-1) Vpr polymorphisms associated with progressors and non-progressor individuals alter Vpr associated functions. J. Gen. Virol. 95:700-711.
Guha D, Klamar CR, Reinhart T,Ayyavoo V. (2015) Transcriptional regulation of CXCL5 in HIV-1-infected macrophages and its functional consequences on CNS Pathology. J. Interferon Cytokine Res. 35:373-384.
Venkatachari NJ, Zerbato JM, Jain S, Mancini AE, Chattopadhyay A, Suis-Cremer N, Bar-Joseph Z,Ayyavoo V. (2015) Temporal transcriptional response to latency reversing agents identifies specific factors regulating HIV-1 viral transcriptional switch. Retrovirol. 12:85.
Jain S, Arrais J, Venkatachari NJ,Ayyavoo V, Bar-Joseph Z. (2016) Reconstructing the temporal progression of HIV-1 immune response pathways. Bioinformatics 32:i253-i261.
Guha D, Mancini A, Sparks J,Ayyavoo V. (2016) HIV-1 infection dysregulates cell cycle regulatory protein p21 in CD4+ T cells through miR-20a and miR-106b regulation. J Cell Biochem 11:1902-1912.
Venkatachari NJ, Jain S, Walker L, Bivalkar-Mehla S, Chattopadhyay A Bar-Joseph Z, Rinaldo C Ragin A, Seaberg E, Levine A, Becker J, Martin E, Sacktor N,Ayyavoo V. (2017) Transcriptome analyses identify key cellular factors associated with HIV-1 associated neuropathogenesis in infected men. AIDS 31:623-633.
Guha D, Wagner MC,Ayyavoo V (2018) Human Immunodeficiency virus type 1 (HIV-1) mediated neuroinflammation dysregulates neurogranin and induces synaptodendritic injury. J neuroinflammation 15: 126
For a full list publications, click this link: https://www.ncbi.nlm.nih.gov/pubmed/?term=ayyavoo+v