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Sickle Cell Disease and Sickle Cell Trait Protection Against HIV-1-infection in Africans and African Americans

Award Number: R01HL125005
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/05/2014
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Sickle Cell Disease and Sickle Cell Trait Protection Against HIV-1-infection in Africans and African Americans - Sickle cell disease (SCD) is an inherited hemoglobinopathy that leads to sickling of red blood cells and the development of chronic hemolytic anemia. SCD patients have lower risk for HIV-1 infection, but its underlying molecular mechanisms are not well understood. We recently showed that changes in iron metabolism leads to upregulation of innate immune response and prevent ex vivo HIV-1 infection of PBMCs obtained from SCD patients. Our working hypothesis is that hemolysis-mediated upregulation of ferroportin expression and iron export in SCD leads to the inhibition of HIV-1 replication. We further hypothesize that macrophage processing of abnormal sickle hemoglobin leads to interferon-β production and stimulation of antiviral response. What is yet unclear is whether SCD or sickle cell trait triggers an overall antiviral state or whether HIV-1 is controlled at post infection stage. To answer these questions, we will investigate HIV-1+ SCD patients and cohort of HIV-1+ sickle cell trait individuals to include males and Africans. We will also utilize mouse model of SCD to analyze EcoHIV-1 infection in vivo. In Specific Aim 1, we will analyze HIV-1 restriction in HIV-1+ SCD individuals. We will analyze the effect of SCD on HIV-1 infection in SCD HIV-1+ patients recruited from Howard University and Montefiore clinics. We will analyze their hematological and virological parameters and test host genes expression using RNA-Seq analysis. We will analyze their HIV-1 phylogeny, HLA-B alleles and inflammation markers. In Specific Aim 2, we will determine the effect of sickle cell trait on HIV-1 infection in African Americans and Africans and viral load in African Americans from WIHS, Multicenter Cohort AIDS Study (MACS), and a Nigerian cohort. We will conduct multivariable analysis to determine the effect of the trait on viral load, relationship to CD4/CD8 counts and levels of proteins involved in iron metabolism and HIV-1 restriction. We will also conduct a case control study to analyze HIV-1phylogeny and the effect of iron and inflammation markers on HIV-1 progression. In Specific Aim 3, we will analyze molecular mechanisms of HIV-1 inhibition in SCD and sickle cell trait. We will analyze expression of host HIV-1 restriction factors in monocyte- derived macrophages treated with HbSS and HbAS hemoglobin and test selected factors in ex vivo HIV-1 infection of PBMCs derived from SCD patients and HIV-1+ sickle cell trait participants from WIHS and MACS cohorts. We will also test HIV-1 infection in SCD and trait mouse models using EcoHIV virus that infects mice and leads to the latent HIV-1 infection in T cells and macrophages.The proposed research will elucidate the molecular mechanisms of HIV-1 inhibition in the settings of SCD and sickle cell trait, which could lead to novel anti-HIV-1 therapeutics based on the concept of HIV-1 restriction mediated by hemolysis and interferon induction by sickle cell hemoglobin.


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: 2025 ( Subtotal = $0 )
2025	2024	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	10	2/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $682,111 )
2024	2024	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	002	10	6/20/2024	NON-COMPETING CONTINUATION	$68,211
2024	2024	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	001	10	2/28/2024	NON-COMPETING CONTINUATION	$613,900
2024	2022	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	8	2/28/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $682,111

Issue Date FY: 2023 ( Subtotal = $684,145 )
2023	2023	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	001	9	3/6/2023	NON-COMPETING CONTINUATION	$684,145
2023	2022	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	8	3/5/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $684,145

Issue Date FY: 2022 ( Subtotal = $686,095 )
2022	2022	HOWARD UNIVERSITY (INC)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	8	3/10/2022	NON-COMPETING CONTINUATION	$617,483
2022	2022	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	001	8	5/24/2022	NON-COMPETING CONTINUATION	$68,612
														Subtotal = $686,095

Issue Date FY: 2021 ( Subtotal = $693,795 )
2021	2021	HOWARD UNIVERSITY (INC)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	7	2/25/2021	NON-COMPETING CONTINUATION	$693,795
														Subtotal = $693,795

Issue Date FY: 2020 ( Subtotal = $718,249 )
2020	2020	HOWARD UNIVERSITY (INC)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	001	6	5/11/2020	COMPETING CONTINUATION	$0
2020	2020	HOWARD UNIVERSITY (INC)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	6	3/30/2020	COMPETING CONTINUATION	$718,249
2020	2020	HOWARD UNIVERSITY (INC)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	004	6	9/24/2020	COMPETING CONTINUATION	$31,856
2020	2020	HOWARD UNIVERSITY (INC)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	002	6	7/9/2020	COMPETING CONTINUATION	$0
2020	2018	HOWARD UNIVERSITY (INC)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	003	5	9/24/2020	NON-COMPETING CONTINUATION	-$31,856
														Subtotal = $718,249

Issue Date FY: 2018 ( Subtotal = $576,697 )
2018	2018	HOWARD UNIVERSITY (THE)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	5	4/12/2018	NON-COMPETING CONTINUATION	$576,697
														Subtotal = $576,697

Issue Date FY: 2017 ( Subtotal = $634,744 )
2017	2017	HOWARD UNIVERSITY, INC.	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	002	4	3/22/2017	NON-COMPETING CONTINUATION	$576,697
2017	2017	HOWARD UNIVERSITY, INC.	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	3	12/15/2016	SUPPLEMENT FOR EXPANSION	$58,047
2017	2017	HOWARD UNIVERSITY, INC.	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	001	3	2/16/2017	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $634,744

Issue Date FY: 2016 ( Subtotal = $433,249 )
2016	2016	HOWARD UNIVERSITY	2244 TENTH STREET, NW ROOM 337	WASHINGTON	DC	20001	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	3	3/7/2016	NON-COMPETING CONTINUATION	$433,249
														Subtotal = $433,249

Issue Date FY: 2015 ( Subtotal = $429,720 )
2015	2015	HOWARD UNIVERSITY	2244 TENTH STREET, NW ROOM 337	WASHINGTON	DC	20001	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	001	2	6/12/2015	SUPPLEMENT FOR EXPANSION	$57,883
2015	2015	HOWARD UNIVERSITY	2244 TENTH STREET, NW ROOM 337	WASHINGTON	DC	20001	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	2	2/6/2015	NON-COMPETING CONTINUATION	$371,837
														Subtotal = $429,720

Issue Date FY: 2014 ( Subtotal = $377,500 )
2014	2014	HOWARD UNIVERSITY	2244 TENTH STREET, NW ROOM 337	WASHINGTON	DC	20001	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	1	5/2/2014	NEW	$377,500
														Subtotal = $377,500

Grand Total All Awards = $5,916,305

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Sickle Cell Disease and Sickle Cell Trait Protection Against HIV-1-infection in Africans and African Americans

Award Number: R01HL125005

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/05/2014

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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