The brain is a major target for HIV infection, with involvement resulting in significant neuropathological changes and a wide range of clinical neurological symptoms, including HIV-related neurocognitive impairment. The neurotoxic effects of HIV proteins can result in neuronal degeneration which can potentially contribute significantly to the development of cognitive impairment. With the introduction of HAART the incidence of HIV associated dementia has decreased, but the prevalence has actually risen due to the increased survival of individuals with cognitive impairment. It is therefore essential to develop treatment approaches that are not only effective in suppressing HIV infection but that are also neuroprotective and can potentially promote repair of HIV-induced nervous system damage. In this application we will evaluate the efficacy of brain derived neurotrophic factor (BDNF) in suppressing nervous system abnormalities that can be observed with HIV infection. This will be done utilizing the HIV transgenic rat model, which has been shown to develop specific nervous system and immune abnormalities that are similar to those seen with the infection in humans. BDNF is a neurotrophin which promotes the development of new neuronal and glia formation and increases neuronal survival. We have developed a method for culturing a pure population of CD34+ bone marrow stem cells (BMSCs) and for genetically engineering the cells and using them as a vehicle for delivering BDNF gene into the central nervous system of small mammals. For these studies we propose the following specific aims:
Aim 1 : Establish and characterize conditional expression of BDNF by BMSC in the CNS of HIV-1 transgenic (Tg) rats;
Aim 2 : Examine the effects of the transduced, BDNF-expressing BMSC on nervous system structural and functional abnormalities in the HIV Tg rat. These studies will be important for delineating the potential efficacy of this neurotrophin and the application of stem cell technologies to the treatment of neurological complications related to HIV infection.
HIV infection is frequently associated with the development of significant neurological abnormalities. These abnormalities can be effectively modeled in the HIV-1 transgenic rat, which contains a non-infectious HIV genome. In this application we will examine the effect treating these abnormalities with brain derived neurotrophic factor which will be secreted by genetically engineered bone marrow stem cells that will be transplanted into the brains of the rats.
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