Elucidating how HIV-1 infection influences CD4, CD8 and regulatory T cell phenotype and function

  • Author / Creator
    Shima Shahbaz
  • Human Immunodeficiency Virus (HIV) infection is still a global health issue. Although the advent of highly active antiretroviral therapies (HAART) to suppress viral replication has transformed HIV infection from a lethal disease to a chronic and manageable infection, it does not cure HIV. CD8 T cells are the crucial cells in mediating immune responses against viral infections; however, in the setting of chronic conditions such as HIV infection, their function is compromised. One potential mechanism associated with CD8 T cell impairment is the upregulation of several co-inhibitory receptors on their surface. Our group has previously shown that Galectin-9 (Gal-9) on regulatory T cells (Tregs) interacts with TIM-3 on CD8 T cells to render them dysfunctional. Thus, we decided to further study the role of Gal-9 on CD8 T cells in HIV-infected individuals. As a comparison, we also investigated the expression of other co-inhibitory receptors. Our data confirmed a higher proportion of CD8 T cells expressing a wide range of co-inhibitory receptors in HIV-infected individuals. In addition, for the very first time, we observed significant abundance of Gal-9 and VISTA, a recently discovered co-inhibitory receptor, expressing CD4 and CD8 T cells in HIV-infected individuals. We further showed that Gal-9 and VISTA expression on CD8 T cells was associated with a dysfunctional phenotype characterized by lower production of inflammatory cytokines and cytotoxic molecules. In contrast, we found a lower proportion of CD73 expressing CD8 T cells in HIV-infected patients, which was due to a decrease in the CD73 gene expression. Our further investigations to determine the mechanism(s) that result in the downregulation of CD73 revealed that the high plasma ATP in HIV-infected individuals downregulates CD73 through the up-regulation of miR-30b,30c, and 30e in CD8 T cells. CD73 is an ectoenzyme that works in tandem with CD39 to convert ATP to adenosine that has immunomodulatory properties. It also functions as a co-signalling and adhesion molecule on T cells, leading to lymphocyte homing to different tissues, such as the brain and lymph nodes. Since CD4 T cells in the gut and lymph nodes constitute major reservoirs of HIV, the loss of CD73 on CD8 T cells may contribute to HIV persistence due to the limited of CD8 T cell access to the viral reservoirs. Therefore, our results demonstrate that HIV infection via mechanisms intrinsic to T cells impairs their effector functions. Moreover, to determine the role of regulatory T cells (Tregs) as the most important extrinsic regulatory element of T cells, we investigated transcription profile and functional properties of Tregs in different subpopulations of HIV-infected individuals (e.g.either receiving antiretroviral therapy (ART) or Long-term non-progressors (LTNPs)). Our RNAseq analysis revealed that Tregs exhibit different transcription profiles in HIV-infected individuals compared to healthy controls. While Tregs from patients on ART upregulate pathways associated with a more suppressive (activated) phenotype, Tregs in LTNPs exhibit upregulation of pathways associated with impaired suppressive properties. These observations may identify Tregs as one potential mechanism for the impaired functionality of CD8 T cells in HIV-infected individuals on ART. Thus, we believe that understanding the extrinsic and intrinsic mechanisms that lead to CD8 T cells dysfunction may pave the way for finding potential therapeutic strategies in HIV-infected individuals.

  • Subjects / Keywords
  • Graduation date
    Fall 2021
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.