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A nonhuman primate model of stem cell transplantation to understand determinants of post-transplant SIV clearance

Award Number: R01AI129703
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY With the most people ever in history currently living with HIV, stopping the HIV epidemic remains imperative. Combination antiretroviral therapy (cART) limits viral replication, but is not curative. Thus, there is an urgent need to design a functional cure via elimination of the viral reservoir. Timothy Brown, aka the Berlin Patient, remains HIV free in the absence of cART following leukemia-related, MHC-matched, allogeneic hematopoietic stem cell transplantation (HSCT) from a CCR5 deficient donor. The mechanisms underlying this functional cure are not known, but may depend on the immune conditioning regimen, graft-versus-host immunity, or a reconstituted immune system lacking CCR5. Non-human primates are the best model of HIV infection, but previous transplant studies have used autologous or MHC-mismatched allogeneic HSCT due to the complexity of non-human primate MHC. Also, no CCR deficient macaque donors exist. Thus, no studies have been able to recapitulate the transplant of Timothy Brown. We have built an allogeneic HSCT model using a novel, Mauritian cynomolgus macaque (MCM). MCM have extremely simplified genetics due to a recent bottleneck approximately 500 years ago. Furthermore, we are currently using CRISPR technology to generate CCR5 deficient donors. Therefore, we are uniquely positioned to recapitulate Timothy Brown’s transplant in a clinically relevant animal model. In specific aim 1, we will measure the impact of myeloablative chemotherapy on clearing the latent viral reservoir in autologous HSCT transplants. In specific aim 2, we will perform fully MHC-matched HSCT, measure graft-versus host immunity, and correlate it to SIV rebound in the plasma and tissues. In specific aim 3, we will use our CCR5 deficient donors to perform an allogeneic HSCT with stem cells lacking CCR5. Overall, this study will allow us to map the determinants of HIV clearance following HSCT.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $874,173 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	003	7	6/21/2023	NON-COMPETING CONTINUATION	$874,173
2023	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	6	11/17/2022	COMPETING CONTINUATION	$0
2023	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	002	6	3/23/2023	COMPETING CONTINUATION	$85,713
2023	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	001	5	3/23/2023	NON-COMPETING CONTINUATION	-$85,713
														Subtotal = $874,173

Issue Date FY: 2022 ( Subtotal = $837,954 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	001	6	7/12/2022	COMPETING CONTINUATION	$837,954
2022	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	5	6/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $837,954

Issue Date FY: 2021 ( Subtotal = $950,729 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	5	11/20/2020	NON-COMPETING CONTINUATION	$950,729
														Subtotal = $950,729

Issue Date FY: 2020 ( Subtotal = $946,593 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	4	11/21/2019	NON-COMPETING CONTINUATION	$785,596
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	001	4	7/21/2020	NON-COMPETING CONTINUATION	$160,997
														Subtotal = $946,593

Issue Date FY: 2019 ( Subtotal = $796,277 )
2019	2019	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	3	11/20/2018	NON-COMPETING CONTINUATION	$796,277
														Subtotal = $796,277

Issue Date FY: 2018 ( Subtotal = $825,078 )
2018	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	001	2	7/3/2018	NON-COMPETING CONTINUATION	-$38,706
2018	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	2	11/22/2017	NON-COMPETING CONTINUATION	$863,784
														Subtotal = $825,078

Issue Date FY: 2017 ( Subtotal = $851,904 )
2017	2017	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	1	12/21/2016	NEW	$851,904
														Subtotal = $851,904

Grand Total All Awards = $6,082,708

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A nonhuman primate model of stem cell transplantation to understand determinants of post-transplant SIV clearance

Award Number: R01AI129703

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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