The project integrates efforts from groups in academia and in industry to develop and perform initial testing of a new agent aimed at the eradication of HIV-1. In broad terms, the objective of the effort is to resolve both basic science and translational issues that represent obstacles between a potential cure for AIDS and clinical practice. On the one hand, 14 years of epidemiologic evidence and clinical efficacy of a small-molecule antagonist have shown that the product of the human CCR5 gene is absolutely required for productive infection by HIV-1. Furthermore, an allogeneic, fully myeloablative bone marrow transplant from a person homozygous for a deletion of CCR5 has completely eradicated the virus from an HIV-positive person. In addition, using an approach known as """"""""genome editing with zinc finger nucleases,"""""""" the CCR5 gene can be distrupted in a targeted fashion in both primary T cells and hematopoietic progenitor/stem cells (HPSCs) to produce knockout cells that resist virus infection ex vivo and in vivo, thus potentially making it feasible to engineer a person's own HPSCs for HIV resistance. The specific goal of the effort is to determine a critical number: what fraction of transplanted HPSCs need to be CCR5 knockouts to eradicate the virus? To answer this question, a study needs to be performed in a clinically relevant nonhuman primate model of HIV infection. Zinc finger nucleases will be engineered and optimized to knock out the CCR5 gene in the pigtailed macaque. Delivery methodology will be worked out to drive this knockout in macaque HPSCs. To allow a controlled experiment in addressing the """"""""fraction of CCR5 knockout cells transplanted vs efficiency of HIV1 eradication,"""""""" procedures and reagents will be built to knock out CCR5 via the targeted integration of a selectable marker that will allow a starting population of HPSCs harboring 5% CCR5-knockout cells to be selected for in live animals to increase the fraction of HIV-resistant cells in the blood. Safety studies will be performed to determine whether the gene disruption leads to undesired effects. At the conclusion of the proposed work, a clear translational path will have been established to eradicate HIV1 by using autologous bone marrow transplantation combined with targeted CCR5 gene disruption.

Public Health Relevance

The project integrates efforts from groups in academia and in industry to develop and perform initial testing of a new agent aimed at the eradication of HIV-1. In broad terms, the objective of the effort is to resolve both basic science and translational issues that represent obstacles between a potential cure for AIDS and clinical practice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096111-03
Application #
8497602
Study Section
Special Emphasis Panel (ZAI1-JBS-A)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$183,191
Indirect Cost
$24,700
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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
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
Dimitrov, Dobromir T; Kiem, Hans-Peter; Jerome, Keith R et al. (2016) A curative regimen would decrease HIV prevalence but not HIV incidence unless targeted to an ART-naïve population. Sci Rep 6:22183
Stone, Daniel; Niyonzima, Nixon; Jerome, Keith R (2016) Genome editing and the next generation of antiviral therapy. Hum Genet 135:1071-82
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
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
Johnston, Christine; Harrington, Robert; Jain, Rupali et al. (2016) Safety and Efficacy of Combination Antiretroviral Therapy in Human Immunodeficiency Virus-Infected Adults Undergoing Autologous or Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies. Biol Blood Marrow Transplant 22:149-56
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
Peterson, Christopher W; Haworth, Kevin G; Burke, Bryan P et al. (2016) Multilineage polyclonal engraftment of Cal-1 gene-modified cells and in vivo selection after SHIV infection in a nonhuman primate model of AIDS. Mol Ther Methods Clin Dev 3:16007
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

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