Complement components are elevated in the brain in a variety of neurodegenerative disorders but their contribution to neuropathogenesis is unknown. Recent studies indicate that C1q and C3 contribute to synaptic remodeling during development and mediate some specific forms of synaptic damage during disease. Consistent with these findings, we have shown that C3 is elevated a) in the brain during HIV-1-associated dementia;b) in mice infected with chimeric HIV-1;and c) in primary human and mouse astrocytes exposed to HIV-1 in culture. Our preliminary data also indicate that HIV-1 induces C3 in astrocytes indirectly through a NF-:B dependent pathway that correlates with production of interleukin 6 (IL-6). Based on the finding that synaptic remodeling during normal brain development requires C3, we hypothesize that C3 overexpression in the brain during HIV infection initiates ectopic synaptic remodeling and neuropathogenesis. In this application, we propose exploratory studies toward testing this hypothesis in two Specific Aims: 1. We will determine the mechanism of C3 induction in astrocytes by intact HIV-1 and Tat with focus on the potential role of HIV-1-induced IL-6 as a mediator. 2. We will identify a mouse model of HIV-1-associated neuropathogenesis that is most suitable for study of C3 and IL-6 induction by HIV-1 or Tat in the brain and the deposition of activated complement in synapses. The proposed exploratory studies should establish the conceptual basis and experimental tools for detailed investigation of the role of complement and its potential inducers HIV and IL-6 in HIV mediated neuropathogenesis. The studies will include experiments with HIV and Tat in primary astrocytes in culture and will evaluate three existing small animal models of HIV neuropathogenesis including transplant of HIV-1-infected syngeneic astrocytes into the mouse brain, transplant of Tat-expressing syngeneic astrocytes into the mouse brain, and direct infection of mice by chimeric HIV-1. Each system will employ wildtype, C3 knockout, and IL-6 knockout mice. Research disciplines involved in this project include retrovirology, molecular biology, neurobiology, neuropathology, and animal studies. The project addresses the growing public health problem of HIV-associated neurocognitive disorders. If successful, the small animal models characterized in this work may be employed for translational research on treatments designated to counter the potential neurodegenerative actions of complement and IL-6 in the brain.

Public Health Relevance

HIV-1 infection continues as a world-wide pandemic. It is disturbing to learn that the incidence of new infections has been under-estimated in the United States and the rate is actually increasing over recent years in New York. Thus this scourge remains a serious Public Health challenge. This application addresses one disorder that persists among HIV-1-infected people, neurocognitive disorders. Nervous system dysfunction can arise from outright cell death, but recent studies also indicate the importance of neuronal functional impairment in the HIV-1- infected brain. This application focuses upon a mechanism of synapse elimination that normally takes place in the developing brain, but may be subverted during HIV-1 infection. This route entails expression of complement component C3, a serum protein found elevated in the brain during HIV-1 infection, as shown here. Proposed are studies on the mechanism of overexpression in primary astrocytes, the most numerous cell in the brain. Turning to understand the impact of this process in the brain, three mouse models of HIV-1 neuropathogenesis will be investigated for the salience of C3 expression and synaptic elimination, a clear path to neurodegeneration. If successful, this developmental application will provide significant leads to counter a new, physiologically relevant pathway of functional impairment of neurons that occurs during HIV-1 infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH086372-02
Application #
7802968
Study Section
Special Emphasis Panel (ZRG1-AARR-H (02))
Program Officer
Joseph, Jeymohan
Project Start
2009-07-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$243,900
Indirect Cost
Name
St. Luke's-Roosevelt Institute for Health Sciences
Department
Type
DUNS #
623216371
City
New York
State
NY
Country
United States
Zip Code
10019