In this U19 application we propose to build upon our expertise in nonhuman primate stem cell transplantation (pigtail macaques), and carefully evaluate the effects of pretransplant conditioning regimens on the HIV reservoir. Our private sector partner will develop ZFNs capable of modifying the macaque CCR5 locus, and optimize methods for their delivery to CD34[+] stem cells. Combining these efforts, we will then perform autologous transplantation in macaques using the CCR5-modfied stem cells. In this way, we hope to recapitulate the well-known Berlin experiment, but using autologous cells such that this approach could be applied to the vast majority of HIV-infected individuals who do not have matched CCR5A32 donors. At the same time, we will develop SHIV-specific homing endonucleases that can directly modify proviral sequences within infected cells (rendering the provirus nonfunctional), and optimize methods for delivery of these HEs to CD4+ T cells and to CD34+ stem cells. We will then test the ability of these HEs to purge provirus from infected cells, using PBMC and stem cells obtained from the macaques in our transplant studies. This is a complex and highly interactive program bringing together experts in multiple fields. Thus, a strong administrative structure is critical to the successful performance of this work.
The aims of the core are: SA1. Ensure that the U19 functions efficiently using effective administrative, fiscal, and scientific review procedures. SA2. Ensure that the U19 investigators communicate effectively with each other, with the broader scientific and clinical communities, with other collaborators, and with the program sponsor, NIH. SAS. Ensure that investigators in the U19 adhere to the highest ethical standards in conducting their research. The Administrative Core will coordinate the administrative, fiscal and organizational aspects of our U19 program, will facilitate scientific communication, and will provide fixed support services to each of the projects and cores. Our integrated research program includes leading scientists based at the FHCRC, the UW, Seattle Children's, City of Hope, and Sangamo Biosciences. Administrative staff members in the Core will provide a bridge between these institutions. All are experienced in coordination of the administrative complexities that a combined program creates.

Public Health Relevance

The overall application proposes a realistic set of experiments offering a potential pathway to the cure of HIV infection. The project is complex, and a well-organized core is critical to its success.

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 #
8691713
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
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:
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
Peterson, Christopher W; Wang, Jianbin; Norman, Krystin K et al. (2016) Long-term multilineage engraftment of autologous genome-edited hematopoietic stem cells in nonhuman primates. Blood 127:2416-26
Adair, Jennifer E; Waters, Timothy; Haworth, Kevin G et al. (2016) Semi-automated closed system manufacturing of lentivirus gene-modified haematopoietic stem cells for gene therapy. Nat Commun 7:13173
Romano Ibarra, Guillermo S; Paul, Biswajit; Sather, Blythe D et al. (2016) Efficient Modification of the CCR5 Locus in Primary Human T Cells With megaTAL Nuclease Establishes HIV-1 Resistance. Mol Ther Nucleic Acids 5:e352
Sedlak, Ruth Hall; Liang, Shu; Niyonzima, Nixon et al. (2016) Digital detection of endonuclease mediated gene disruption in the HIV provirus. Sci Rep 6:20064
Spragg, Chelsea; De Silva Feelixge, Harshana; Jerome, Keith R (2016) Cell and gene therapy strategies to eradicate HIV reservoirs. Curr Opin HIV AIDS 11:442-9
De Silva Feelixge, Harshana S; Stone, Daniel; Pietz, Harlan L et al. (2016) Detection of treatment-resistant infectious HIV after genome-directed antiviral endonuclease therapy. Antiviral Res 126:90-8
Stone, Daniel; Niyonzima, Nixon; Jerome, Keith R (2016) Genome editing and the next generation of antiviral therapy. Hum Genet 135:1071-82

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