Investigation of the Role of Myeloid and T Cells in Human Immunodeficiency Virus (HIV) Infection and Persistence in Vivo

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  • March 19, 2019
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  • Honeycutt, Jenna
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Human immunodeficiency virus (HIV) infection is the causative agent of AIDS and readily infects CD4+ T cells. I have characterized a humanized T cell only mouse (ToM) model that I have used to better understand pathogenesis of HIV infection in T cells. HIV infection is maintained over the lifetime of these animals, and viral replication is controlled using antiretroviral therapy. I have also demonstrated that latent HIV infection is readily established in ToM and that discontinuation of ART in these mice results in rapid viral rebound. These observations demonstrated that the presence of human myeloid-derived cells is not necessary for effective HIV replication or for HIV persistence in vivo. However, T cells are not the only targets of infection, and previous studies have indicated that macrophages represent another target for infection as these cells express the cell surface receptors for HIV entry, CD4 and CCR5. Recent evidence that presence of virus in macrophages may be attributed to phagocytosis of T cells by macrophages and not to productive infection has highlighted the need for a careful re-evaluation of HIV infection of macrophages. I characterized the susceptibility of NOD/SCID mice reconstituted with human CD34+ stem cells to infection with HIV. These mice are devoid of human (and mouse) T cells, and I established that replication in this model occurs in tissue macrophages. I have established that only macrophage-tropic HIV isolates are able to replicate in these mice, HIV is present systemically, and viral replication is sustained over time. Since the only targets for HIV infection present in these mice are of myeloid origin, they have been designated as myeloid-only mice (MoM). Treatment with antiretroviral therapy in MoM results in the rapid depletion of virus in plasma and tissues. Removal of therapy resulted in delayed viral rebound, demonstrating that macrophages are a source of viral rebound after ART-interruption. Overall, I present herein two new and complementary models of HIV infection: ToM and MoM. These two models along with the humanized bone marrow/liver/thymus (BLT) mouse model, which is reconstituted with human T and myeloid cells, will allow us to establish definitive roles for T cells and myeloid cells in multiple areas of research including mucosal transmission, viral persistence, and new therapies for treatment or for cure.
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  • In Copyright
Advisor
  • Eron, Joseph
  • Murdoch, David
  • Wan, Yisong
  • Garcia-Martinez, J. Victor
  • Collins, Edward
  • De Paris, Kristina
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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  • There are no restrictions to this item.
Date uploaded
  • January 21, 2016

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