Transcriptome and functional profiles of R/G-HIV+ human astrocytes: Implications for shock or lock therapies in the brain

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dc.contributor.advisorBorgmann, Kathleen
dc.contributor.committeeMemberBerg, Rance E.
dc.contributor.committeeMemberKrishnamoorthy, Raghu R.
dc.contributor.committeeMemberMathew, Porunelloor A.
dc.contributor.committeeMemberYang, Shaohua
dc.contributor.committeeMemberPatterson, Rita M.
dc.creatorEdara, Venkata Viswanadh
dc.creator.orcid0000-0001-9321-7839 (Edara, Venkata Viswanadh)
dc.date.accessioned2021-05-13T21:17:25Z
dc.date.available2021-05-13T21:17:25Z
dc.date.issued2020-05
dc.description.abstractA significant number of people living with human immunodeficiency virus (HIV) suffer from HIV-associated neurocognitive disorders (HAND). Many previous studies investigating HIV in astrocytes as a heterogenous population have established the relevance of astrocytes to HIV-associated neuropathogenesis. However, these studies were unable to differentiate the state of infection, i.e. active or restricted, or to evaluate how this affects astrocyte biology. In this study a pseudotyped doubly labelled fluorescent reporter R/G-HIV-1 was used to identify and enrich restricted and active populations of HIV+ astrocytes based on the viral promoter activity. Here we report, the majority of human astrocytes restricted R/G-HIV-1 gene expression early during infection and were resistant to reactivation by vorinostat and interleukin-1β. However, actively infected astrocytes were inducible, leading to increased expression of viral proteins upon reactivation. R/G-HIV-1 infection also significantly decreased cell proliferation and glutamate clearance ability of astrocytes, which may contribute to excitotoxicity. Moreover, transcriptome analyses to compare gene expression patterns of astrocytes harboring active vs restricted long terminal repeats revealed that the gene expression patterns were similar, and the active population demonstrated more widespread and robust changes. Our data suggest that harboring the HIV genome profoundly alters astrocyte biology and strategies that keep the virus latent (e.g. Block and Lock), or those that reactivate the latent virus (e.g. Shock and Kill) may be detrimental to astrocyte function and possibly augment their deleterious contributions to HAND.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/30746
dc.language.isoen
dc.subjectastroglia
dc.subjectHIV-1 latency
dc.subjectHIV-associated neurocognitive disorders (HAND)
dc.subjectneuroinflammation
dc.subjecttranscriptomics
dc.subjectviral reservoirs
dc.subject.meshAstrocytes
dc.subject.meshHIV-1
dc.subject.meshNeurocognitive Disorders
dc.titleTranscriptome and functional profiles of R/G-HIV+ human astrocytes: Implications for shock or lock therapies in the brain
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplineBiomedical Sciences
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy

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