The goal of this project is to evaluate strategies to eliminate HIV and latent reservoirs in a monkey model of HIV/SHIV infection. Recent promising vaccine trials have failed to protect from HIV, emphasizing the importance of developing alternative therapies. One such alternative therapy is the genetic modification of hematopoietic cells to make them resistant to HIV infection. Genetic modification of hematopoietic stem cells (HSCs) with zinc finger nucleases targeting the CCR5 gene loci have been shown to reduce the severity of disease in an HIV mouse model system. Thus, we propose a study aimed at determining the potential clinical application of a gene modifying approach targeting CCR5 as an antiviral therapy with the overall goal being the eradication of the viral reservoir in HIV[+] patients. We will study the effect of CCR5[-/-] repopulating cells on the latent reservoir using a clinically relevant nonhuman primate AIDS model, the pigtailed macaque (M. nemestrina). This model will allow us to carefully and thoroughly analyze the impact of CCR5[-/-] hematopoietic reconstitution on the control of HIV/SHIV. Here we will address several crucial questions regarding the feasibility and translatability of this approach. We will evaluate methods to efficiently modify HSCs in a large animal model, determine the engraftment potential of ZFN-modified HSCs and the level of ZFN-modified repopulating cells necessary for efficient control of HIV. Given the high clinical relevance of the SHIV macaque model, these studies should be readily translatable to the understanding of latency in HIV/AIDS patients. This project complements and interacts closely with the other projects and cores. Specifically, data from Project 1 will serve as a baseline for the latent reservoir in monkeys, Project 2 will provide and develop novel reagents. Project 4 will develop anti HIV strategies that can be incorporated into the monkey studies and Project 5 will develop novel delivery approaches which can also be tested in monkeys. This project will make use of all the cores. We propose the following four aims: 1) Determine the optimal approach for genetically modifying hematopoietic stem cells with zinc finger nucleases. 2) Determine the engraftment potential of ZFN-modified CCR5[-/-] repopulating cells in macaques. 3) Establish means to efficiently and safely increase the percentage of CCR5-modified cells. 4) Determine if transplantation with CCR5[-/-] CD34[+] cells can prevent infection and provide long-term control.

Public Health Relevance

The goal of this project is to evaluate strategies to eliminate HIV. Despite the best efforts by the scientific community, an effective vaccine against HIV has remained elusive. Recent promising vaccine trials have failed to protect from HIV, emphasizing the importance of developing alternative therapies. This study proposes the genetic modification of hematopoietic cells to make them resistant to HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096111-04
Application #
8691706
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98109
Colonna, Lucrezia; Peterson, Christopher W; Schell, John B et al. (2018) Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation. Nat Commun 9:4438
Paul, Biswajit; Ibarra, Guillermo S Romano; Hubbard, Nicholas et al. (2018) Efficient Enrichment of Gene-Modified Primary T Cells via CCR5-Targeted Integration of Mutant Dihydrofolate Reductase. Mol Ther Methods Clin Dev 9:347-357
Dubé, Karine; Dee, Lynda; Evans, David et al. (2018) Perceptions of Equipoise, Risk-Benefit Ratios, and ""Otherwise Healthy Volunteers"" in the Context of Early-Phase HIV Cure Research in the United States: A Qualitative Inquiry. J Empir Res Hum Res Ethics 13:3-17
Adair, Jennifer E; Kubek, Sara P; Kiem, Hans-Peter (2017) Hematopoietic Stem Cell Approaches to Cancer. Hematol Oncol Clin North Am 31:897-912
Reeves, Daniel B; Peterson, Christopher W; Kiem, Hans-Peter et al. (2017) Autologous Stem Cell Transplantation Disrupts Adaptive Immune Responses during Rebound Simian/Human Immunodeficiency Virus Viremia. J Virol 91:
Niyonzima, Nixon; Lambert, Abigail R; Werther, Rachel et al. (2017) Tuning DNA binding affinity and cleavage specificity of an engineered gene-targeting nuclease via surface display, flow cytometry and cellular analyses. Protein Eng Des Sel 30:503-522
Peterson, Christopher W; Benne, Clarisse; Polacino, Patricia et al. (2017) Loss of immune homeostasis dictates SHIV rebound after stem-cell transplantation. JCI Insight 2:e91230
Reeves, Daniel B; Duke, Elizabeth R; Hughes, Sean M et al. (2017) Anti-proliferative therapy for HIV cure: a compound interest approach. Sci Rep 7:4011
Dubé, Karine; Taylor, Jeff; Sylla, Laurie et al. (2017) 'Well, It's the Risk of the Unknown… Right?': A Qualitative Study of Perceived Risks and Benefits of HIV Cure Research in the United States. PLoS One 12:e0170112
Chiarelli, Peter A; Revia, Richard A; Stephen, Zachary R et al. (2017) Nanoparticle Biokinetics in Mice and Nonhuman Primates. ACS Nano 11:9514-9524

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