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. / Microbiology and Immunology
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/3960 |
| Date | January 2016 |
| Creators | Tashovski, Ivan |
| Contributors | Tsygankov, Alexander Y., Chin, Mario, Ganea, Doina, Eisenstein, Toby K., Xiao, Weidong, Ward, Sara Jane |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 148 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/3942, Theses and Dissertations |
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