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Reducing Latent Viral Reservoirs in Infant Macaques

Award Number: R01HD080459
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2014
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Reducing Latent Viral Reservoirs in Infant Macaques - PROJECT SUMMARY Cocktails of antiretroviral drugs (ART) have been successful in reducing viremia to undetectable levels in HIV+ adult subjects who have access to them and who can remain adherent. Yet, the suppressive drugs are unable to eliminate latent virus in cellular and tissue compartments and are thus required for continued remission. While ART is the standard of care for HIV+ mothers and their infants who are exposed to infection risk before, during, and after birth, it has not been possible to test the impact on viral reservoirs upon treatment interruption. We have developed a robust, reproducible nonhuman primate (NHP) model for transmission in utero, peripartum and breastfeeding, in order to examine new therapeutic regimens for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Passively transferred bNAbs can provide sterilizing immunity when used as PrEP in nonhuman primate models, and have also been recently shown to prevent the establishment of viral reservoirs when given as PEP within days of viral exposure. Studies designed to understand the mechanism of action of antibodies is a critical next step. The central hypothesis of this research proposal is that novel, orthogonal therapeutic treatment with ART, a CCR5-blocking antibody, and potent neutralizing human monoclonal antibodies (bNAbs) will result in highly controlled viremia and undetectable viral reservoirs in babies born to HIV-infected mothers. Newborn and infant rhesus macaques when infected orally with SHIVSF162P3 develop widely dispersed and rapidly diverging viral quasispecies in blood and tissues within the first few days to weeks of infection, resulting in high and persistent viremia. However, in newborn macaques that receive ART or bNAbs at 24-30 hours after exposure, permanent viral seeding is prevented, but delays in treatment result in rebound upon treatment cessation. The project will explore the effects of combination and sequential treatment with ART, Leronlimab, and bNAbs, which we predict will result in prevention of viral reservoir establishment when used as PrEP, and in reduction or elimination of viral reservoirs when used as PEP in the first few weeks after virus exposure. We will show the effects of reduced infectious centers by in vivo imaging with positron emission tomography and compare these results with standard virological assays and RNAscope imaging. Ulimately, we hope that this combination therapy will lead to translation into the clinic so that HIV-exposed and vertically infected babies can be treated for limited periods of time and experience durable viral remission without further treatment.


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: 2027 ( Subtotal = -$25,763 )
2027	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	10	10/19/2026	NON-COMPETING CONTINUATION	-$25,763
														Subtotal = -$25,763

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	001	10	7/17/2025	NON-COMPETING CONTINUATION	$0
2025	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	10	7/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $859,479 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	001	10	8/7/2024	NON-COMPETING CONTINUATION	$8,594
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	10	7/2/2024	NON-COMPETING CONTINUATION	$850,885
														Subtotal = $859,479

Issue Date FY: 2023 ( Subtotal = $860,650 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	9	7/17/2023	NON-COMPETING CONTINUATION	$860,650
														Subtotal = $860,650

Issue Date FY: 2022 ( Subtotal = $857,506 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	8	7/26/2022	NON-COMPETING CONTINUATION	$857,506
														Subtotal = $857,506

Issue Date FY: 2021 ( Subtotal = $858,801 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	003	7	8/27/2021	NON-COMPETING CONTINUATION	$17,177
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	002	7	6/30/2021	NON-COMPETING CONTINUATION	$841,624
2021	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	001	6	1/21/2021	COMPETING CONTINUATION	$101,168
2021	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	5	1/21/2021	NON-COMPETING CONTINUATION	-$101,168
														Subtotal = $858,801

Issue Date FY: 2020 ( Subtotal = $851,722 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	6	5/1/2020	COMPETING CONTINUATION	$851,722
														Subtotal = $851,722

Issue Date FY: 2018 ( Subtotal = $1,311,373 )
2018	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	5	7/6/2018	NON-COMPETING CONTINUATION	$1,311,373
														Subtotal = $1,311,373

Issue Date FY: 2017 ( Subtotal = $1,215,319 )
2017	2017	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	4	7/5/2017	NON-COMPETING CONTINUATION	$1,215,319
														Subtotal = $1,215,319

Issue Date FY: 2016 ( Subtotal = $1,234,993 )
2016	2016	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	3	6/1/2016	NON-COMPETING CONTINUATION	$1,234,993
														Subtotal = $1,234,993

Issue Date FY: 2015 ( Subtotal = $1,194,483 )
2015	2015	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	2	6/5/2015	NON-COMPETING CONTINUATION	$1,194,483
														Subtotal = $1,194,483

Issue Date FY: 2014 ( Subtotal = $941,882 )
2014	2014	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	1	7/31/2014	NEW	$941,882
														Subtotal = $941,882

Grand Total All Awards = $10,160,445

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Reducing Latent Viral Reservoirs in Infant Macaques

Award Number: R01HD080459

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2014

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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