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AAV-mediated delivery of eCD4-Ig for prevention and treatment of perinatal HIV infection

Award Number: R01HD102252
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Mother-to-child transmission of human immunodeficiency virus (HIV) still results in hundreds of thousands of new pediatric HIV infections every year, especially in resource-poor areas of the world where access to antenatal/postnatal antiretroviral therapy (ART) is limited. Sadly, in the absence of ART, >50% of HIV- infected infants die by 2 years of age. Since ART alone will not be sufficient to end the morbidity and mortality associated with HIV/AIDS in children, there is an urgent need for developing practical interventions to prevent and treat pediatric HIV infection. To that end, this project will evaluate the potential of gene therapy with the potent and extremely broad HIV inhibitor eCD4-Ig to prevent and treat perinatal HIV infection. eCD4-Ig is a chimeric molecule consisting of the outer domains of CD4, an IgG Fc portion, and a co-receptor mimetic peptide. eCD4-Ig has unmatched breadth and very potent effector activities against HIV-1, HIV-2, and SIV. The eCD4-Ig gene will be delivered to infant rhesus macaques (RMs) via adeno-associated virus (AAV)-mediated gene transfer. AAV vectors are safe and can transduce both dividing and non-dividing cells. Critically, AAV-driven transgene expression in long-lived cells, such as those of skeletal muscle, can last for years, possibly decades. While AAV-mediated delivery of eCD4-Ig has been shown to protect adult RMs against challenge with pathogenic immunodeficiency viruses bearing highly divergent envelope proteins, this approach has never been tested in infants. We have recently partnered with the Farzan lab to characterize the kinetics of eCD4-Ig expression in infant RMs treated with AAV/eCD4-Ig at birth. Compared to adult animals, AAV/eCD4-Ig-treated newborn RMs experienced substantially higher levels of eCD4-Ig and lower levels of antibodies against the eCD4-Ig molecule. Note that these anti-drug antibodies (ADAs) are highly detrimental to AAV-mediated delivery of immunoglobulins because they can clear the molecules from circulation, thereby reducing the efficacy of this approach. The low levels of ADAs observed in the AAV/eCD4-Ig-treated infants is consistent with previous reports of neonates developing tolerance to AAV-delivered transgene products. Given the ability of AAV vectors to promote sustained transgene expression after a one-time administration, and the unique window of opportunity offered by the neonatal period to achieve robust AAV-driven expression of eCD4-Ig in vivo, we postulate that AAV-mediated delivery of eCD4-Ig to infants can prevent and treat postpartum HIV infection. In specific aim (SA) 1, we will characterize the safety profile of AAV/eCD4-Ig in infant RMs. In SA 2, we will determine if neonatal delivery of AAV/eCD4-Ig can prevent oral acquisition of SIVmac239 in RMs. In SA 3, we will assess if AAV-mediated delivery of eCD4-Ig to SIV-infected infant RMs can control viral replication without ART. If successful, the proposed experiments will build the pre-clinical foundation for testing AAV-mediated gene therapy with eCD4-Ig in infants as a means to prevent and treat perinatal HIV infection.


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 = $825,105 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Child Health and Human Development Extramural Research	002	5	5/19/2023	NON-COMPETING CONTINUATION	$825,106
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Child Health and Human Development Extramural Research	000	4	12/6/2022	NON-COMPETING CONTINUATION	$0
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Child Health and Human Development Extramural Research	001	2	1/3/2023	NON-COMPETING CONTINUATION	-$1
														Subtotal = $825,105

Issue Date FY: 2022 ( Subtotal = $818,853 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Child Health and Human Development Extramural Research	002	4	8/29/2022	NON-COMPETING CONTINUATION	$818,853
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Child Health and Human Development Extramural Research	000	2	8/2/2022	NON-COMPETING CONTINUATION	-$353,525
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Child Health and Human Development Extramural Research	001	3	8/2/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$353,525
														Subtotal = $818,853

Issue Date FY: 2021 ( Subtotal = $824,261 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Child Health and Human Development Extramural Research	000	2	5/17/2021	NON-COMPETING CONTINUATION	$824,261
														Subtotal = $824,261

Issue Date FY: 2020 ( Subtotal = $835,519 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Child Health and Human Development Extramural Research	000	1	8/7/2020	NEW	$835,519
														Subtotal = $835,519

Grand Total All Awards = $3,303,738

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AAV-mediated delivery of eCD4-Ig for prevention and treatment of perinatal HIV infection

Award Number: R01HD102252

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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