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Mechanisms of altered immune responses in HIV exposed infants

Award Number: R21HD083344
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: 03/25/2015
PERIOD OF PERFORMANCE END DATE: 11/30/2018

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Mechanisms of altered immune responses in HIV exposed infants - ¿ DESCRIPTION (provided by applicant): Although prevention of mother-to-child-transmission (PMTCT) with antiretroviral therapy has successfully reduced maternal HIV transmission, this leaves approximately 1.6 million HIV-exposed but uninfected (HEU) infants born annually. Despite the success of PMTCT, these children are not healthy. They are more likely to die or become sick during the first few months of life when compared to HIV-unexposed (HU) children and this is regardless of the mother's health or socioeconomic status. The vulnerability of these infants represents a major public health burden. We regard the unhealthy status of HEU infants to be based on a dysfunctional immune system, as these children respond poorly to vaccinations. Consequently, this study will focus on specific immunological abnormalities in these newborn infants. We have preliminary data showing that T cells in HEU newborn infants are highly activated, but have impaired function. We speculate that this is due to HIV exposure during pregnancy, or due to chronic maternal inflammation. We aim to seek a mechanism for impaired T cell immunity in these unhealthy infants and hypothesize that immune activation in the newborn results in increased frequencies of naturally occurring suppressor/regulatory cell populations, and that this is the basis for dysfunctional immunity. We will study the frequency and function of Myeloid Derived Suppressor Cells (MDSC) and T regulatory (Treg) cells and the effect these have on the infant's immunity to vaccines. Such an approach is entirely novel and our ability to explore newborn infant immunity will provide insight into how the health of these children is compromised. To address this hypothesis, we will use our established clinic in Khayelitsha, Cape Town, and enroll 100 HEU and 50 HU controls and follow them over 36 weeks. We will compare proportions of suppressor/regulatory cells and activated T cells at birth and after vaccination between HEU and healthy HU infants (Aim 1). We will collect cord blood to establish the immune status at birth and then measure T cell responses to Tetanus Toxoid and BCG on follow-up. We will also explore further mechanisms that result in the possible disruption of T cell functional pathways, by comparing the function and gene expression profiles of whole blood, MDSC and Treg cells between HEU and HU (Aim 2). We will use this approach to identify potential mechanisms to account for the inability of T cells in the HEU infant to functionally respond to vaccine antigens. This study brings together a wealth of expertise with investigators in the US and South Africa who are authorities in clinical, immunological and genomic analyses. This joint approach will be used to investigate the immune response of HIV-exposed infants to seek a mechanism for poor immunity at birth in these infants. The knowledge and insight gained from this study will lay the foundation for developing treatment strategies in these vulnerable children.


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: 2022 ( Subtotal = -$534 )
2022	2016	UNIVERSITY OF CAPE TOWN	LOVERS WALK	RONDEBOSCH				ZAF	Child Health and Human Development Extramural Research	000	2	10/1/2021	NON-COMPETING CONTINUATION	-$534
														Subtotal = -$534

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2016	UNIVERSITY OF CAPE TOWN	LOVERS WALK	RONDEBOSCH		007700		ZAF	Child Health and Human Development Extramural Research	000	2	2/28/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	UNIVERSITY OF CAPE TOWN	LOVERS WALK	RONDEBOSCH		007700		ZAF	Child Health and Human Development Extramural Research	000	2	3/8/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $190,964 )
2016	2016	UNIVERSITY OF CAPE TOWN	LOVERS WALK ROAD	CAPETOWN				ZAF	Child Health and Human Development Extramural Research	000	2	3/1/2016	NON-COMPETING CONTINUATION	$190,964
														Subtotal = $190,964

Issue Date FY: 2015 ( Subtotal = $223,899 )
2015	2015	UNIVERSITY OF CAPE TOWN	LOVERS WALK ROAD	CAPETOWN				ZAF	Child Health and Human Development Extramural Research	000	1	3/25/2015	NEW	$223,899
														Subtotal = $223,899

Grand Total All Awards = $414,329

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Mechanisms of altered immune responses in HIV exposed infants

Award Number: R21HD083344

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: 03/25/2015

PERIOD OF PERFORMANCE END DATE: 11/30/2018

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