PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is becoming a major cause of death in persons with HIV-1 infection. The mechanisms that link HIV-1 infection, CVD and activation of the immune system associated with HIV infection (immune activation) remain unknown. Despite effective antiretroviral therapy (ART) there is persistent immune activation that is associated with CVD progression. It is becoming increasingly clear that markers of activation of monocyte/macrophages (M/M) may more accurately predict morbidity and mortality than T-cell parameters in ART-treated individuals. M/M co-localize with oxidized lipids (oxPLs) in tissues such as arteries and the gut, one of the largest reservoirs in HIV-1 infection that harbors most of the body's M/M. Emerging evidence suggests that formation of oxidized lipids in gut may regulate inflammation and CVD. M/M also interact with oxidized lipoproteins and are at the intersection between HIV-1 infection, gut related and systemic inflammation, CVD and immune activation. Unraveling how oxidized lipids affect M/M, CVD and HIV-1 pathogenesis may contribute to development of new therapies to manage HIV-related CVD. Such therapies include High Density Lipoprotein (HDL) mimetic peptides that mimic normal functions of HDL such as binding of oxPLs and anti-inflammatory properties. We hypothesize that HIV-1 and oxidized lipids foster a vicious cycle of HIV-1-enhanced M/M activation and inflammation that drive CVD in HIV-1 infected individuals. The overall goal is to explore whether HIV-1 infection drives increased formation of oxidized lipids and proinflammatory/ proatherogenic M/M despite effective ART. This project is organized into two aims. Aim 1 will explore in a humanized mouse model in vivo whether HIV-1, despite effective ART, directly induces formation of oxidized lipids that is attenuated by HDL mimetics. Aim 2 will determine in vivo using the same mouse model if HDL mimetics improve prooxidant, proinflammatory, activated and proatherogenic phenotype of M/M in chronic treated HIV-1 infection. Given that HIV-1-infected persons on ART may continue to have elevated M/M activation and oxidized lipids, such an approach could reduce the excess morbidity and mortality remaining despite. This work is innovative, has an impact on public health and directly addresses research priorities regarding HIV-associated comorbidities.