PROJECT SUMMARY ABSTRACT
HIV infection results in cardiovascular/ pulmonary complications, with over 75% of patients with chronic HIV
disease showing clinical manifestations, even when on long-term successful combination antiretroviral therapy
(cART). Endothelial cell dysfunction is central to HIV-associated cardiopulmonary complications. Compromised
endothelial cells result in increased leukocyte transmigration, HIV infection, and the establishment of a highly
inflammatory environment, which further aggravates HIV-associated cardiopulmonary disease, including accel-
erated aging or “inflammaging”. Extracellular vesicles are secreted from nearly every cell type. Many types of
extracellular vesicle exist, which we shall refer to collectively as EVs. They are released into the circulation,
influencing intercellular communication at both local and distant sites from their cellular source. Thus, pulmonary
endothelial cells, and the underlying parenchyma are constantly exposed to EVs. Infection with SIV or HIV can
affect the composition of EVs, facilitating viral pathogenesis and spread. EVs from productively-infected cells in
peripheral reservoir sites, including lymph nodes and GI tract, can contain viral proteins, host microRNAs and
proteins that trigger responses in the heart and lung, all of which can promote inflammaging. Our team of collab-
orators showed this for EVs circulating in HIV-associated cancer patients and animal models, and in aviremic
human patients. It is reasonable to assume that EVs containing viral proteins, including Nef, could contribute to
HIV-associated cardiopulmonary complications. Several studies have demonstrated that these proteins inde-
pendently trigger distinct changes in endothelial cell function through upregulation of adhesion molecules, se-
cretion of cytokines and activation of caspase 3. However, EV production, composition and function, especially
in the context of successful cART suppression of SIV infection, represents a significant gap in our knowledge.
Therefore, there is a critical need to understand the role of EVs in pathogenesis of SIV-associated cardiopulmo-
nary disease and how cART influences SIV EV-induced intercellular communication. This R01 application, which
piggy-backs on several NIH-funded projects, seeks to address how long-term successful cART influences EV
cargo and how EV from SIV-infected cells induce inflammaging, focusing on endothelial cell dysfunction.