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    BAG6 as a Novel HIV-1 Host Factor

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    Genre
    Thesis/Dissertation
    Date
    2016
    Author
    Tashovski, Ivan
    Advisor
    Tsygankov, Alexander Y.
    Committee member
    Chin, Mario
    Ganea, Doina
    Eisenstein, Toby K.
    Xiao, Weidong
    Ward, Sara Jane
    Department
    Microbiology and Immunology
    Subject
    Microbiology
    Virology
    Biology, Molecular
    Cannabinoids
    Hiv-1
    Host Factors
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/3960
    
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    DOI
    http://dx.doi.org/10.34944/dspace/3942
    Abstract
    The human immunodeficiency virus type-1 (HIV-1) is the major etiological agent of acquired immunodeficiency syndrome (AIDS), the cause of over 30 million deaths worldwide. Highly active antiretroviral therapy (HAART) has demonstrated great efficacy at suppressing viral load and is therefore the standard therapeutic treatment for HIV-1 infection. Noncompliance due to severe HAART-associated side effects significantly undermines therapeutic efficacy. Dronabinol, the synthetic form of the cannabinoid THC found in marijuana, is FDA-approved for countering some of these side effects. Studies have reported that cannabinoids restrict HIV-1 replication, although no mechanism has yet been proposed. Thus the purpose of this study was to characterize the effects of cannabinoids on HIV-1 infection and to determine the molecular basis of cannabinoid-induced viral suppression. By transcriptomic sequencing of T cells treated with cannabinoids, we have found that the expression of BAG6, a protein uncharacterized within the context of HIV-1 infection, was downregulated. To identify the role of this protein during infection, we knocked down BAG6 and were able to recapitulate the protective effects of cannabinoids by observing reduced severity of viral challenge. Moreover, we have also identified BAG6 to be a binding partner of two HIV-1 viral accessory proteins, Vif and Vpr. Importantly, we have discovered that Vpr mediates targeted degradation of BAG6 by leveraging the host proteasome during the early stages of the viral lifecycle, revealing a hitherto unknown function of this poorly-understood viral protein. We thus establish modulation of BAG6 expression as a novel mediator of the effects of cannaninoids on HIV-1 infection.
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