HIV-1 associated neuropathogenesis is characterized by two distinct observations. The first concerns the notable cognitive and motor dysfunction in HIV-1 infected individuals. The second relates to the lack of infection of neurons by HIV-1. This suggests that the dementia in AIDS patients might be the result of a combination of both direct and indirect effects of HIV-1 encoded proteins (Env, Tat, Nef and Vpr) and host cellular factors. The mechanisms underlying the onset and progression of dementia are poorly understood. The goal of this application is to elucidate the contribution of HIV-1 Vpr to neuropathogenesis. In the infected individuals, Vpr is present in cell-associated, virion-associated and cell and virion-free forms. Further, the ability to traverse through cell membrane endows Vpr the potential to cause damage directly in uninfected bystanders such as neurons. Furthermore, Vpr is also known to indirectly dysregulate bystander cells through cellular factors released from infected target cells. Based on this, we hypothesize that Vpr has the potential to contribute to neuronal apoptosis and dysfunction. To elucidate the molecular events underlying dementia, we propose to analyze the effects of Vpr using appropriate human primary cells in culture as a model. To achieve these goals we propose to: (i) determine the mechanism(s) involved in Vpr mediated neuronal loss and dysfunction directly;(ii) identify the cellular cofactors and neuroinflammatory molecules differentially regulated by Vpr in target cells;and (iii) identify the structure-function relation of Vpr to neuropathogenesis using naturally occurring Vpr variants from CNS compartment.

Public Health Relevance

Dramatic improvements in treating HIV-1 infected individuals have been attained with Highly Active Anti-Retroviral Therapy (HAART), and despite the availability of HAART, neurocognitive disorders affect 50-70% of the HIV-1 infected individuals. High incidence of HIV-Associated Dementia (HAD) is due to the neuronal dysfunction caused by the viral proteins as well as the inflammatory factors released by the infected cells into the local environment. Therefore, a combination therapy targeting both viral and neuroinflammatory factors would be desirable. This study focuses on understanding the role of viral and host cellular factors in neuropathogenesis toward identifying novel targets and designing new therapeutics against HIV-1 in the central nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH087247-02
Application #
8041009
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Joseph, Jeymohan
Project Start
2010-03-09
Project End
2015-02-28
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
2
Fiscal Year
2011
Total Cost
$338,995
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Guha, Debjani; Wagner, Marc C E; Ayyavoo, Velpandi (2018) Human immunodeficiency virus type 1 (HIV-1)-mediated neuroinflammation dysregulates neurogranin and induces synaptodendritic injury. J Neuroinflammation 15:126
Venkatachari, Narasimhan J; Jain, Siddhartha; Walker, Leah et al. (2017) Transcriptome analyses identify key cellular factors associated with HIV-1-associated neuropathogenesis in infected men. AIDS 31:623-633
Guha, Debjani; Mancini, Allison; Sparks, Jessica et al. (2016) HIV-1 Infection Dysregulates Cell Cycle Regulatory Protein p21 in CD4+ T Cells Through miR-20a and miR-106b Regulation. J Cell Biochem 117:1902-12
Guha, Debjani; Klamar, Cynthia R; Reinhart, Todd et al. (2015) Transcriptional Regulation of CXCL5 in HIV-1-Infected Macrophages and Its Functional Consequences on CNS Pathology. J Interferon Cytokine Res 35:373-84
Venkatachari, Narasimhan J; Zerbato, Jennifer M; Jain, Siddhartha et al. (2015) Temporal transcriptional response to latency reversing agents identifies specific factors regulating HIV-1 viral transcriptional switch. Retrovirology 12:85
Hadi, Kevin; Walker, Leah A; Guha, Debjani et al. (2014) Human immunodeficiency virus type 1 Vpr polymorphisms associated with progressor and nonprogressor individuals alter Vpr-associated functions. J Gen Virol 95:700-11
Guha, Debjani; Ayyavoo, Velpandi (2013) Innate immune evasion strategies by human immunodeficiency virus type 1. ISRN AIDS 2013:954806
Zych, Courtney; Domling, Alexander; Ayyavoo, Velpandi (2013) Development of a robust cell-based high-throughput screening assay to identify targets of HIV-1 viral protein R dimerization. Drug Des Devel Ther 7:403-12
Mehla, Rajeev; Ayyavoo, Velpandi (2012) Gene array studies in HIV-1 infection. Curr HIV/AIDS Rep 9:34-43
Guha, Debjani; Nagilla, Pruthvi; Redinger, Carrie et al. (2012) Neuronal apoptosis by HIV-1 Vpr: contribution of proinflammatory molecular networks from infected target cells. J Neuroinflammation 9:138