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    HIV-1 gp120 Mediated Neuronal Deregulation: Unraveling the Molecular Mechanisms Involved

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    Genre
    Thesis/Dissertation
    Date
    2016
    Author
    Shrestha, Jenny
    Advisor
    Sawaya, Bassel E.
    Committee member
    Rogers, Thomas J., 1950-
    Soboloff, Jonathan
    Smith, George M.
    Kirby, Lynn
    Department
    Molecular Biology and Genetics
    Subject
    Biology, Molecular
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/3563
    
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    DOI
    http://dx.doi.org/10.34944/dspace/3545
    Abstract
    The advancement in combinatory antiretroviral therapy (cART) has granted people with HIV-1 an improved lifespan by decreasing the likelihood of AIDS-defining illnesses. People diagnosed early in their infection and undergo cART can keep the virus suppressed and live as long as their HIV-negative peers. As of 2015, more than 50% of people living with HIV in the United States are aged 50 and older. With improved life expectancy, individuals living with long-term HIV infection exhibit many clinical characteristics commonly observed in aging such as: cardiovascular disease, lung disease, certain cancers, HIV-Associated Neurocognitive Disorders (HAND), and liver disease (including hepatitis B and hepatitis C), among others. Regarding neurocognitive disorders, HIV/AIDS patients seem to have learning deficits and working memory impairment such as easy forgetfulness and slowness in action, difficulties in concentration, planning, and multitasking in the condition of having a relatively uneventful and well-controlled clinical course with low HIV viral titers. Neuropsychological studies have disclosed cognitive impairment in a substantial (15–50%) proportion of patients, including learning and working memory deficits which may affect their quality of life, adherence to treatment and ultimately result in increased comorbidity. Studies have described cAMP responsive-element binding (CREB)-1 protein - involved in mitochondrial biogenesis, long-term memory and synaptic plasticity - as a key player in protecting neurons and preventing neurodegeneration. However, loss of CREB protein expression and phosphorylation leads to the development of neurocognitive impairments such as learning deficit and working memory alteration. CREB performs its functions by regulating several genes such, PGC-1 and BDNF being the few (key regulators of mitochondrial bioenergetics, synaptic plasticity and long-term memory, respectively). In here, we have shown that exposure of neuronal cells and animals to HIV-1 gp120 protein decreases expression level of phosphorylated CREB and inhibits its function. Therefore, it will lead to altered neuronal communication and mitochondrial functions. Using pharmacological reagent – rolipram (activates cAMP by inhibiting PDE-4), we were able to reverse the effect of Gp120. Rolipram treatment restored CREB expression and functions altered by gp120. During my graduate years, using in vitro and in vivo studies, I was able to determine the mechanisms used by gp120 leading to the loss of; i – energy metabolism; ii – synaptic plasticity; and iii – long-term memory. We partially determined the relation between gp120, CREB and downstream targets of CREB (PGC-1α and/or BDNF). This approach allowed me to further understand the relation between gp120 and mitochondria as well as between gp120 and neuronal communication. Overall, our study has marked a milestone with regards to understanding the role of gp120 and learning deficiency. Our study mechanistically unravels for the first time the relation between HIV-gp120 protein and development of cognitive disorders such as declarative memory impairment that is commonly observed in HIV-1 patients as well as in aged people. Using an intervention (rolipram) approach, to prevent CREB loss of functions, will help establish new therapeutic strategy (high throughput screening) to mitigate cognitive impairments associated with HIV-1 infection in HIV/AIDS patients.
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