Hematopoietic cell transplant (HCT) has been reported to have purged the reservoir of latently HIV-infected cells in one patient who received an HIV-resistant graft. For this approach to become broadly feasible, it is imperative that we determine the factors involved in HCT that contribute to eradication of the reservoir. Project 1 aims to determine what components of HCT are critical for elimination of the latent viral reservoir. The broad aim of Project 1 is to develop a platform for delivery of HIV-resistant cells to replace latently infected cells. In order to accomplish this broad goal, it is imperative that we determine the role of the separate mechanisms that may contribute to long-term elimination of the reservoir: 1) intensive chemo/radiotherapy which may eradicate recipient lymphocytes and dendritic or antigen presenting cells; and 2) reconstitution of immunity with HIV-uninfected and HIV-resistant cells. We hypothesize that both dose-intensity and graft source contribute separately to elimination of latently infected cells.
In Specific Aim 1, we will investigate in human subjects both 1) the dose-intensity of conditioning that produces a meaningful reduction in the quantity of latent viral infection, and 2) the role of the graft source in eliminating latently infected cells.
In Specific Aim 2, the effect of a lymphoablative conditioning on latently SHIV infection will be studied carefully in a macaque model, so as to separate the role of conditioning from the role of the graft source. Finally, we hypothesize that, in the absence of HIV-resistant cells, the latent reservoir ultimately will be replenished over time by low level replication of virus.
In Specific Aim 3, we will investigate the source of HIV responsible for replenishing the latent reservoir, by a phylogenetic analysis of viral sequences obtained from blood, cerebral spinal fluid, and the intestinal tract, before and after HCT. Result from Project 1 will be used together with that from Project 5 to develop a clinical protocol for delivery of genetically modified HIV resistant cells. Project 1 will rely heavily on Core A and Core B, for support of the primate experiments. The phylogenetic sequencing and analysis will be performed by Core C.

Public Health Relevance

To date, only one successful cure for HIV has been reported, that of an HIV-infected patient given an allogeneic hematopoietic cell transplant (HCT) from a CCR5n32 homozygous donor. The objective of Project 1 is to investigate HCT as a method to purge the latent HIV reservoir. Ultimately knowledge gained from Project 1 will be used to develop a platform for transplantation of HIV-resistant cells.

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 #
8691704
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
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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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