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
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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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