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Assessing if distinct susceptibility to neutralization of cell-free and cell-to-cell spread impacts antibody conferred protection from SHIV infection

Award Number: K01OD031900
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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PROJECT SUMMARY/ABSTRACT Antiretroviral therapy-based pre-exposure prophylaxis (PrEP) is a highly effective biomedical HIV prevention strategy. However, many individuals at high risk of HIV acquisition are not receiving PrEP due to multiple issues, including potential drug toxicity, adherence and cost. As such, there is a need to develop additional safe and effective biomedical HIV prevention strategies. Major prevention strategies currently in development include the provision or induction of anti-viral neutralizing antibodies by passive immunization or vaccination, respectively. The utility of neutralizing antibodies for preventing HIV infection has been validated in nonhuman primates. Passively transferred antibodies protect nonhuman primates from oral, vaginal, rectal and intravenous challenges with simian human immunodeficiency virus (SHIV). Antibody conferred protection is primarily due to blockade of the viral entry process but can also involve the elimination of infected cells or virions via antibody Fc dependent functions. An often overlooked issue in preclinical nonhuman primate studies of neutralizing antibody conferred protection from SHIV challenge is that human HIV infections are a consequence of exposure to infectious bodily fluids containing both cell-free and cell-associated virus. The viruses that initiate new HIV infections are termed transmitted founder (TF) viruses. Preliminary data assessed in vitro neutralization of cell- free and cell-to-cell spread of a panel of SHIVs with envelopes from TF HIVs using the PGT121 anti-HIV neutralizing antibody. For several of these viruses, PGT121 fully neutralized cell-free spread but did not neutralize cell-to-cell spread. The proposed research will assess if distinct neutralization of cell-free and cell-to- cell viral spread impacts the ability of a neutralizing antibody to prevent infection following in vivo viral exposure. This work will use one of the TF SHIVs, SHIVBG505, to perform cell-free or cell-associated challenges in rhesus macaques infused with PGT121, an isotype control or a version of PGT121 with abrogated/diminished Fc dependent functions. The central hypotheses are: (I) PGT121 will prevent infection following cell-free SHIVBG505 challenge; (II) PGT121 will not prevent infection following cell-associated SHIVBG505 challenge; and (III) Fc dependent functions will contribute to the outcomes of cell-free or cell-associated SHIVBG505 challenges. These hypotheses will be evaluated across three specific aims: (I) assess if PGT121 protects rhesus macaques from challenge with cell-free SHIVBG505; (II) assess if PGT121 protects rhesus macaques from challenge with cell- associated SHIVBG505; and (III) determine the impact of Fc dependent functions on the outcome of cell-free or cell-associated SHIVBG505 challenges in PGT121 infused rhesus macaques. Generated data will contribute to the development of antibody-based HIV prevention tools, by providing a refined definition of the characteristics of neutralizing antibodies required to achieve protection. This work will be done at the Yerkes National Primate Research Center and is a key piece of the candidate's career development plan. The candidate's long-term goal is to fully transition into an independent investigator.


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 = $213,057 )
2023	2023	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Research Infrastructure Programs	001	3	5/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$213,057
2023	2023	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Research Infrastructure Programs	003	3	7/26/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$196,163
2023	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Research Infrastructure Programs	002	2	7/26/2023	NON-COMPETING CONTINUATION	-$196,163
2023	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Research Infrastructure Programs	000	2	5/10/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $213,057

Issue Date FY: 2022 ( Subtotal = $213,057 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Research Infrastructure Programs	001	2	6/2/2022	NON-COMPETING CONTINUATION	$21,306
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Research Infrastructure Programs	000	2	3/10/2022	NON-COMPETING CONTINUATION	$191,751
														Subtotal = $213,057

Issue Date FY: 2021 ( Subtotal = $213,057 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Research Infrastructure Programs	000	1	5/12/2021	NEW	$213,057
														Subtotal = $213,057

Grand Total All Awards = $639,171

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Assessing if distinct susceptibility to neutralization of cell-free and cell-to-cell spread impacts antibody conferred protection from SHIV infection

Award Number: K01OD031900

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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