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    Human T Helper 17 Cells Are Highly Permissive to Productive Human Immunodeficiency Virus Infection

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    Author
    Christensen-Quick, Aaron Robert
    Advisor
    Garzino-Demo, Alfredo
    Date
    2015
    Type
    dissertation
    
    Metadata
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    Abstract
    Human Immunodeficiency Virus (HIV) infects and depletes CD4+ T cells, but subsets of CD4+ T cells vary in their susceptibility and permissiveness to infection. For example, HIV preferentially infects effector/memory T cells in the Gut Associated Lymphoid Tissue (GALT). IL-17-producing "T helper 17" (Th17) cells are enriched within the GALT, and are highly susceptible to HIV. The preferential depletion of Th17 cells during the acute phase of infection is associated with impairment of the integrity of the gut mucosal barrier, which drives chronic immune activation - a key determinant of disease progression. The preferential loss of Th17 cells has been attributed to high CD4, CCR5, and CXCR4 receptor expression, paired with low expression of HIV-inhibitory co-receptor ligands. Here we show that Th17 cells also exhibit heightened permissiveness to productive HIV infection. Primary human CD4+ T cells were sorted, activated in Th17- or Th0-polarizing conditions and infected, then analyzed by flow cytometry. Th17-polarizing cytokines increased HIV infection, and HIV infection was significantly higher among Th17 cells compared with IL-17- or IFNγ+ cells, even upon infecting with a replication-defective, envelope-pseudotyped HIV vector. Further, Th17-polarized cells produced more virus. Based on these observations, we hypothesized that the presence of positive effectors of HIV replication (such as a favorable transcriptional environment) in Th17 cells, and/or a relative lack of negative effectors (such as antiviral immune defenses) could contribute to their permissiveness to HIV. Microarray and immunoblot analyses performed on Th17- or Th0-polarized CD4+ T cells reveal that Th17-polarized cells have diminished expression of HIV-inhibitory members of the RNase A superfamily. Our findings demonstrate that human, peripheral blood Th17 cells are not only susceptible but also permissive to HIV infection. Our data link gene expression in Th17 cells to increased HIV production, suggesting that Th17 cells might be major sources of viral production during acute infection.
    Description
    University of Maryland, Baltimore. Molecular Microbiology and Immunology. Ph.D. 2015
    Keyword
    CCR6
    Rnase
    RORγt
    Tfh
    HIV
    Ribonucleases
    Th17 Cells
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/4581
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