Approximately 1 in 4 immunosuppressed AIDS patients develop a neurodegenerative disorder clinically characterized as HIV associated dementia complex (HIVD). We theorize that HIVD is due to increased trafficking of HIV-infected monocytes into the brain. Monocytes are activated upon leaving the blood stream and entering the CNS where they transform into macrophages, initiate viral replication and a neuroinflammatory cascade. Tissue damage begins a cycle of astrocytic and microglial activation, providing susceptible targets for further HIV infection and disrupting synaptic connectivity. We propose to use SIV infection of Macaca nemestrina as a model of HIV encephalitis to explore several hypotheses related to our theory of lentiviral neuropathogenesis. Our overarching hypothesis is: Progression of SIV infection leads to increased monocyte/macrophage infection and trafficking into the CNS that is associated with a unique proteomic signature in the CSF.
Specific Aim 1 will compare the proteomic profile of CSF from SIV infected macaques with and without SFV encephalitis using mass spectrometry. We will test the hypothesis that CSF from macaques with encephalitis will have a characteristic proteomic signature reflecting increased macrophage trafficking and viral production.
Specific Aim 2 will identify the unique protein peaks (biomarkers) that distinguish CSF from encephalitic versus non-encephalitic animals.
Specific Aim 3 will retrospectively compare the CSF biomarker panel sampled at different stages of infection. We hypothesize that 1-2 months prior to terminal infection, CSF proteomic markers of monocyte ingress will antedate the development of CNS disease. These studies will uncover novel biomarkers of encephalitis due to trafficking of SIV infected monocytes into the CNS.
| Bonneh-Barkay, Dafna; Bissel, Stephanie J; Wang, Gouji et al. (2008) YKL-40, a marker of simian immunodeficiency virus encephalitis, modulates the biological activity of basic fibroblast growth factor. Am J Pathol 173:130-43 |
