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Investigating Plasma Cell-Free Hemoglobin as a Driver of Cardiovascular Disease Risk in HIV-Positive Individuals

Award Number: R21AI191916
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/17/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Investigating Plasma Cell-Free Hemoglobin as a Driver of Cardiovascular Disease Risk in HIV-Positive Individuals - PROJECT SUMMARY: People with HIV (PWH) face persistent low-grade inflammation, pro-active blood clotting mechanisms, and a twofold higher risk of cardiovascular disease despite effective anti-HIV treatments. A recent clinical trial showed that statins reduce cardiovascular disease risks by up to 35%, but PWH still face higher risks than non-HIV individuals, revealing gaps in our understanding cardiovascular disease pathogenesis. The persistence of cell free hemoglobin (CFH) above normal physiological thresholds in virologically controlled PWH may be an underappreciated factor contributing to the chronic immune activation and a pro-thrombotic state. To date, a comprehensive knowledge of the causes and pathobiological significance of red blood cell-derived extracellular vesicles (rEVs) containing cell-free hemoglobin in PWH remains elusive. Furthermore, the potential impact of these vesicles on endothelial cells and platelets - resulting in endothelial dysfunction and platelet hyperreactivity - is inadequately understood, despite their association with an increased likelihood of cardiovascular disease pathogenesis in hemolytic anemias without HIV. This proposal centers on the hypothesis that extracellular vesicles, particularly rEVs, might be an additional contributor to endothelial dysfunction and platelet activation in PWH. By addressing this, this study aims to shed light on a previously less recognized CVD risk factor in PWH and would reveal novel translational approaches to mitigate endothelial dysfunction and chronic inflammations. Our central innovation lies in investigating the ability of rEVs and rEV- associated cell free hemoglobin to trigger endothelial and platelet responses, a novel focus that could fill significant knowledge gaps regarding residual cardiovascular disease. In this project’s we initially plan to quantify and characterize rEVs and rEV-associated CFH in PWH and the uninfected control samples and to examine their capacity to elicit endothelial dysfunction and platelet activation by ex vivo experiments. The study will explore correlations between rEV-associated cell free hemoglobin levels and chronic inflammation in PWH. It will investigate whether rEVs cause endothelial dysfunction through free radicals, reactive oxygen species, and TLR4 signaling. Specific Aim 1 involves isolating and analyzing rEVs from PWH and non-HIV controls to test if PWH have higher rEV-bound CFH levels, along with assessing pro-inflammatory cytokine levels. In Specific Aim 2, ex vivo studies will use human aortic endothelial cells and gel-purified platelets to examine rEV-driven dysfunction and activation using gene sequencing, flow cytometry, and Seahorse metabolic assays. The study will leverage de-identified plasma from the Center for AIDs Research sample repository at Case Western Reserve University. We aim to initiate larges insightful studies in the future based on the knowledge gained from this exploratory study. This project aims to uncover residual cardiovascular disease risks in PWH through a retrospective case-control study of 124 plasma samples, offering strategies for clinical intervention to benefit both PWH and non-HIV populations. The findings will broaden our understanding of cardiovascular risks in other systemic, diseases like sickle cell anemia.


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: 2026 ( Subtotal = $235,500 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	1	4/21/2026	NEW	$235,500
														Subtotal = $235,500

Grand Total All Awards = $235,500

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Investigating Plasma Cell-Free Hemoglobin as a Driver of Cardiovascular Disease Risk in HIV-Positive Individuals

Award Number: R21AI191916

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/17/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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