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CMV reactivation in the vasculature of people with HIV drives T cell responses

Award Number: R21AI192237
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: 02/20/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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CMV reactivation in the vasculature of people with HIV drives T cell responses - PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in the United States and worldwide. People with HIV (PWH) with virus suppression on antiretroviral therapy (ART) have a 2-fold increased risk of developing CVD compared to people without HIV (PWoH), even when controlling for age and traditional CVD risk factors. One factor that may contribute to the increased CVD in PWH is cytomegalovirus (CMV) coinfection. Nearly all PWH and about half of all adults without HIV in the United States have CMV, which is independently linked to CVD. In preliminary spatial transcriptomic analyses of vascular tissues of PWH and PWoH, all of whom have peripheral artery disease, we find that the proportion of myeloid cells in regions of interest (ROIs) across arteries is significantly higher in tissues from PWH. CMV can reactivate from latently-infected monocytes as they differentiate into macrophages, and virological and immunological evidence suggests that PWH have more frequent CMV reactivation events than do PWoH, so the cardiopathogenic effects of CMV may be more pronounced among PWH due to the increased numbers of macrophages harboring replicating CMV. We hypothesize that CMV reactivation in infiltrating macrophages provides antigenic signals for CMV-reactive T cells in vascular tissues. We will use the following Specific Aims to test this hypothesis. Aim 1: To define the spatial context of CMV expression in vascular tissues of PWH and PWoH. In Aim 1, we will test this hypothesis by (1) defining the spatial context of CMV expression in situ in vascular tissues of PWH and PWoH with and without CVD, (2) quantifying CMV expression in macrophages in vessels from PWH and PWoH with and without CVD, and (3) confirming spatial relationships of CD4 and CD8 T cells and CMV-expressing target cells in the vasculature. Aim 2. To determine if serum-derived MDMs from PWH with CMV are more effective at activating and presenting CMV antigens to T cells than are MDMs from PWoH with CMV. In Aim 2, we will use in vitro experiments to determine if serum-derived MDMs from PWH with CMV, which preserves the influence of systemic inflammatory mediators, are more effective at activating autologous T cells than MDMs from PWoH with CMV. Then, we will determine if that activation is due to CMV antigen presentation by the serum-derived MDMs, and whether statin treatment of the MDMs, which inhibits CMV replication in vitro, directly impairs their T cell activating capacity. Our studies may define mechanisms whereby chronic viral infection drives T cell- mediated vascular pathology and may identify novel targets beyond traditional risk factors to prevent/treat CVD in PWH and PWoH. Furthermore, understanding the role of CMV in CVD, and whether its activity is susceptible to statins, will help inform the interpretation of the A5332/REPRIEVE (pitavastatin) and A5383/ELICIT (letermovir) trials in PWH.


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 = $233,790 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	1	2/20/2026	NEW	$233,790
														Subtotal = $233,790

Grand Total All Awards = $233,790

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CMV reactivation in the vasculature of people with HIV drives T cell responses

Award Number: R21AI192237

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: 02/20/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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