Impact of Asymptomatic CMV on Cardiovascular Event Risk in Treated HIV

People with HIV (PWH) remain at higher risk for Type 1 myocardial infarction (T1MI), ischemic stroke, and venous thromboembolism (VTE) than the general population despite antiretroviral therapy (ART)-mediated viral suppression. These risks may be accentuated in women with HIV, particularly after the menopausal transition. Systemic inflammation persists in many PWH despite ART and predicts each of these vascular events, but the optimal interventional targets remain unclear. We and others have implicated cytomegalovirus (CMV) co-infection as a potentially important therapeutic target to reduce inflammation-associated vascular disease risk in treated HIV. In particular, our recent clinical trial of the CMV-specific antiviral drug letermovir demonstrated that suppressing asymptomatic CMV reshapes the plasma inflammatory and cardiometabolic proteome, decreasing several inflammatory and angiogenesis pathways that may play a role in both cardiovascular and VTE risk, but whether these changes are causally associated with disease risk in treated HIV infection remains unknown. It also remains unclear whether these CMV-associated pathways are preferentially active in women with HIV. To address these issues, we are leveraging data from our clinical trial of letermovir and are building upon our case-cohort study within the CFAR Network of Integrated Clinical Systems (CNICS) of 1,994 ART-suppressed people with HIV, 485 of whom experienced subsequent vascular events, and all of whom have GWAS data available. With these resources, we will perform by far the largest Mendelian Randomization study to date of causal proteomic predictors of cardiovascular and VTE events in treated HIV, including pathways linked to CMV replication and those that are modified by natal sex. Aim 1 will assess whether CMV-associated plasma proteomic signatures as well as CMV-specific neutralizing antibody titers (a novel measure of prior CMV burden) are associated with incident T1MI, ischemic stroke, and VTE in treated HIV. Aim 2 will assess whether CMV-associated plasma proteins are causally associated with T1MI, ischemic stroke, and VTE by Mandelian Randomization in this setting. Aim 3 will assess sex differences in these CMV-associated plasma inflammatory and cardiometabolic proteins, whether sex modifies the association between these markers and vascular events, and the degree to which the menopausal transition may modify these pathways. These studies leverage a multidisciplinary team with expertise in translational immunology, HIV and CMV pathogenesis, vascular disease, epidemiology, and bioinformatics and will create a resource that can be leveraged by others to assess predictors of other disease outcomes and/or add additional analytes. Collectively, these studies will help clarify the potential clinical implications of CMV-associated biomarker changes, the mechanisms by which sex modifies the relationship between inflammation and vascular diseases, and accelerate the identification of novel interventional targets to reduce multi-morbidity in people with treated HIV. Project Number: 1R01HL180319-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: PETER HUNT | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $2,981,544 | Activity Code: R01 | Study Section: HIV Comorbidities and Clinical Studies Study Section[HCCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL18031901