Abstract: Persons living with HIV (PWH) experience constant stigma and other forms of social rejection elevating psychological stress. The project objective is to model the impact of the psychosocial experiences of stigma and social rejection on the complex interactions between multiple systems (neural, immune, and autonomic) that give rise to atherosclerotic processes in the context of treated chronic HIV-infection. This project assembles a multi-disciplinary team that will decipher the complexity of these interactions within a cohort of 150 PWH between the ages of 35-55 years that have stable anti-retroviral regimens and undetectable viral toads without history of heart failure. The study aims to test two separate psycho-neuro-immune mediation models for experiences of social rejection associated with HIV+ status on carotid plaque formation measured through high resolution ultrasound. In the first model, using an interactive functional magnetic resonance imaging (fMRI) paradigm, peripheral blood monocyte activation and expression of IL-6 will be tested as a mediator of the association between activation of threat-sensitive brain regions to social rejection and carotid plaque formation. In the second model, IL-6 expression over 7-days will be tested as a mediator for the association of ecological momentary assessments (EMA) of everyday experiences of stigma and related stress with carotid plaque formation. The reliability of these models of putative psycho-neuro-immune mechanisms in predicting carotid plaque burden will be assessed at baseline and 3-9 month follow-up. The study further aims to evaluate the potential mitigating role of the acetyl-cholinergic anti-inflammatory pathway on carotid plaque formation by testing whether vagal-mediated heart rate variability (HRV) moderates the associations of neural activation to social rejection {Aim 1) and naturalistic social rejection experiences (Aim 2) with change in proinflammatory cytokine expression. The long-term objectives of this study are two-fold. First, to elucidate the relationships among these biobehavioral determinants of carotid plaque formation in PWH who traditionally are socially rejected due to their HIV positive status. The second tong-term objective is to evaluate the buffering effect HRV on these associations as a biobehavioral target for future interventions in PWH at risk for atherosclerotic CVD.