Investigation of HIV cure strategies in vivo in BLT humanized mice Public Deposited

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  • March 19, 2019
Creator
  • Tsai, Perry
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • There is no cure yet for HIV. The development of HIV cure strategies will be accelerated by the use of animal models for HIV infection and treatment. Here, we investigated several HIV cure strategies in BLT humanized mice. First, we sought to explore the use of CCR5delta32 transplant to cure HIV-infected BLT mice. We found that CCR5delta32 stem cells engrafted in NSG mice and rendered them resistant to HIV infection. However, we were not able to successfully engraft CCR5delta32 cells in infected, suppressed mice. Alternatively, a cure might be achieved by reversing HIV latency, so we tested a latency-reversing agent: histone deacetylase inhibitor panobinostat. Panobinostat treatment resulted in increased histone acetylation in BLT mice, but did not significantly change levels of HIV cell-associated RNA, DNA, or latently infected cells in infected, suppressed BLT mice. Such an approach may require combination with other latency-reversing or cell-killing strategies. Next, we investigated the ability of CD8+ T cells to control HIV infection in BLT mice generated from donors with protective HLA alleles. While these mice did not control wildtype infection, several mice were able to control infection with a nef-deleted virus; and peak viral loads and average viral loads were significantly lower in two cohorts infected with nef-deleted virus. We also detected functional, HLA-restricted, HIV-specific CD8+ T cells in the mice; and viremia increased rapidly in several mice after CD8-depletion. These studies suggest that CD8+ T cells are able to control infection in BLT mice only with nef-deficient virus. A targeted immunological agent may be necessary for CD8+ T cells to kill infected cells. We tested a novel CD19xCD3 dual affinity retargeting (DART) molecule for redirected lysis in BLT mice. DART molecule administration resulted in profound depletion of CD19+ cells in both peripheral blood and tissues, and this depletion was dependent on the presence of CD8+ T cells. Overall, I present herein results from four approaches in HIV cure — allogeneic transplant, latency reversal, CD8+ T cell control, redirected lysis — in BLT humanized mice. This work represents significant progress in the development of BLT humanized mice for use in research toward an HIV cure.
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  • In Copyright
Advisor
  • De Paris, Kristina
  • Eron, Joseph
  • Serody, Jonathan
  • Garcia-Martinez, J. Victor
  • Miao, Edward
  • Goonetilleke, Nilu
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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