This is a R21 application in response to PAR-09-222 entitled 'Cutting-Edge Basic Research Award (CEBRA)'. The main goal of this Phase I CEBRA application is to create and characterize a novel mouse model for studies on the combined impact of HIV infection and drug abuse on adult neurogenesis. Active neurogenesis continues throughout adulthood in both the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus (DG); the latter gives rise to granule cells in the hippocampus, which has been linked to neurocognitive function and is negatively regulated by pathological stimuli such as drug abuse and HIV infection. It is well established that drugs of abuse including opiates, cocaine, and methamphetamine (METH) inhibit adult neurogenesis. In contrast, not much is known about the effects of HIV infection on adult neurogenesis, the responsible viral determinants and the underlying cellular and molecular mechanisms. Furthermore, there is scant information about the combined impact of HIV infection and drug abuse on adult neurogenesis. We have recently established an doxycycline (Dox)-inducible brain-specific HIV-1 Tat bigenic mouse model (iTat) in which Tat expression can be induced to exclusively express in the brain, and we have demonstrated that expression of Tat protein in the brain in the absence of HIV-1 infection is sufficient to induce neurobehavioral and neuropathologies that recapitulate some important features in the brain of HIV-1-infected individuals (Kim et al., Am. J. Path, 162:1693-707, 2003). Our studies suggest a potential inhibitory role of Tat on adult neurogenesis. The overall hypothesis of this project is that HIV Tat interacts with drugs of abuse, leading to decreased neurogenesis in HIV-infected adults and contributing to the neurocognitive dysfunction in these individuals. To test this hypothesis, in this Phase I CEBRA proposal, we propose to create an inducible brain-specific Tat/neuron progenitor cells (NPC)-specific nestin promoter-driven GFP mouse model (iTat/nestin-GFP) by breeding the iTat bigenic mice with nestin-GFP transgenic mice. Direct, convenient and reproducible visualization and tracking of NPC in this new model will provide a unique opportunity for us to study Tat effects and Tat/METH combined effects on adult neurogenesis through characterization of the temporal and spatial distribution, differentiation and survival of NPC in METH-exposed and Tat-expressing iTat/nestin-GFP mice; the functional consequences will be correlated with the neurocognitive function of these mice. Completing the studies will allow us to define the cellular and molecular mechanisms responsible for Tat/METH-altered neurogenesis at Phase II, which we believe will eventually help identify therapeutic approaches (molecules) that promote de novo neurogenesis for functional replacement of HIV-mediated neurodegeneration and prevent, ameliorate, or reverse the complications of HIV- associated dementia or mild cognitive and motor disorders of HIV-infected individuals and HIV-infected drug abusers.
The HIV/AIDS epidemic has posed a great social, economic and political challenge in the 21st century. As of December 2008, 34.0 million adults and 2.1 million children are estimated to have acquired HIV infection worldwide. HIV infection of the brain occurs early in the course of infection and often leads to cognitive, motor, and other behavioral problems. In the era of highly active antiretroviral therapy, a milder form of HIV-associated dementia so-called minor cognitive and motor disorder has become predominant and prevalent among the HIV-infected population. While our understanding of the disease mechanisms remains incomplete, there are no effective therapies to reduce, prevent, or reverse HIV-mediated cognitive, motor and behavioral problems at the present time. On the other hand, HIV infection and drug abuse are interlinked epidemics throughout the world, while each alone is capable of causing cognitive deficits. In this current study, we propose to create a novel mouse model for studies on the connection between HIV infection, drug abuse and cognitive dysfunction. This model shall eventually lead to development of therapeutic strategies to restore the normal cognitive function of HIV-infected individuals and HIV-infected drug abusers.
|Fan, Yan; Gao, Xiang; Chen, Jinhui et al. (2016) HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway. J Neurosci 36:11362-11373|
|Park, In-Woo; He, Johnny J (2010) HIV-1 is budded from CD4+ T lymphocytes independently of exosomes. Virol J 7:234|
|Zou, Wei; Wang, Zhenyuan; Liu, Ying et al. (2010) Involvement of p300 in constitutive and HIV-1 Tat-activated expression of glial fibrillary acidic protein in astrocytes. Glia 58:1640-8|