The pathogenesis of HIV encephalitis (HIVE), a central nervous system (CNS) complication frequently seen in AIDS patients, is incompletely understood. Since neurons are not infected by HIV, but mononuclear phagocytes are, it is hypothesized that these infected mononuclear phagocytes produce a wide variety of putative neurotoxins that damage neurons. Determining the neurotoxin(s) that result in cognitive dysfunction and HIV pathology can lead to better treatments for patients. We hypothesize that the production of interferon-alpha (IFN?) by HIV infected and activated mononuclear phagocytes in the CNS inhibits neuron function and contributes to HIVE. The role of IFN? in HIVE will be examined in neuron cultures and the HIVE SCID mouse model using immunohistochemistry, real-time PCR, animal behavior testing, and antibody treatment. Neuron cultures exposed to HIV infected mononuclear phagocytes will express morphological changes of decreased dendritic arborization and synaptic connections. Blocking IFN? with neutralizing antibodies will recover these morphological changes. SCID mice inoculated with HIV infected human monocytes exhibit HIVE pathology. An anti- IFN? treatment administered intrathecally in mice will block the effects of IFN? on neurons. This research is important because despite intensive research over the last 25 years, a vaccine or treatment has not been developed to prevent or cure HIV. Therefore, better therapies are needed for treating the complications that arise from HIV infection. By examining the effects of cytokine expression during HIVE this research will help determine the mechanisms that result in abnormal cognitive function and may lead to better treatments for HIV patients in the United States and worldwide. ? ? ?
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| Rao, Vasudev R; Sas, Andrew R; Eugenin, Eliseo A et al. (2008) HIV-1 clade-specific differences in the induction of neuropathogenesis. J Neurosci 28:10010-6 |
| Sas, A; Jones, R; Tyor, W (2008) Intra-peritoneal injection of polyclonal anti-interferon alpha antibodies cross the blood brain barrier and neutralize interferon alpha. Neurochem Res 33:2281-7 |
