Project 3 seeks to determine whether gene modification of transplanted CD34+ hemotopoietic stem cells (HSCs) to resist HIV infection combined with gene modification of transplanted CD8+ T cells can function coordinately to block viral rebound following sessation of ART and effectively eradicate HIV reservoirs. Specifically, we will leverage the expertise of Project 2 (novel HSC engraftment conditioning regimens) and Projects 1 and 4 (powerful gene-editing approaches including CRISPR/Cas9) to efficiently modify and engraft HSCs and autologous CD8+ T cells within an HSC transplant approach. We will test these concepts in vivo utilizing the recently developed CD34+ HSC-derived humanized BLT mouse model that recapitulates HIV infection and human immunity to HIV to accomplish the two stages of a `Defend and Destroy? HIV cure strategy: i) defend transplanted cells against future HIV infection by knocking out the HIV co-receptor CCR5 in CD34+ hematopoietic stem cells (HSCs); and ii) enhance the capacity of autologous, mature CD8+ T cells to find and destroy residual HIV infected cells by manipulating genes associated with effector function, mucosal and reservoir homing, and target cell recognition. We hypothesize that the combined approach of limiting viral spread while simultaneously enhancing immune clearance by autologous CD8+ T cell responses has the potential to achieve a functional cure of HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19HL129903-04
Application #
9462624
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Thomas, John
Project Start
Project End
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
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