Doctoral Dissertation Defense | Jennifer Chavez

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Florida International University University Graduate School

Doctoral Dissertation Defense

Abstract Probing the Proteome: Depressive Symptoms, Inflammation & Mitochondrial Perturbations in Acute HIV Infection

by Jennifer Vanessa Chavez

There is ample evidence that HIV-associated pathophysiologic alterations fuel neuropsychiatric comorbidities. During acute HIV infection (AHI) damage to the gut-associated lymphoid tissue causes translocation of microbial products, including lipopolysaccharides, and drives gut-immune dysfunction. Even though antiretroviral therapy (ART) suppresses viral replication, it fails to completely restore gut barrier integrity and normalize plasma immune markers, driving chronic immune activation and inflammation. This proinflammatory state is made worse by a marked reduction in antioxidants and upregulation of ROS and/or reactive nitrogen species, affecting mitochondrial function. Additionally, substance use also increases HIV pathogenesis in the central nervous system (CNS) despite ART. Proteomics, the evaluation of the function and structure of proteins to understand an organism’s nature, has been leveraged to examine HIV-associated outcomes across the lifespan. However, much of the existing literature has focused on individuals with chronic, treated HIV infection, making it challenging to disentangle the biological processes initiated by HIV itself from the compounded effects of chronic infection, prolonged ART use, aging and comorbid conditions. Examining the earliest stages of HIV infection provides a unique opportunity to characterize initial neuroimmune events that may precede long-term neuropsychiatric complications, like depressive symptoms. Therefore, the overarching goal of this dissertation is to examine how peripheral molecular processes beyond inflammation and immune activation, including immunometabolic, lipid and systemic metabolism, mitochondrial and neuroendocrine mechanisms, during AHI may contribute to depressive symptoms and concurrent brain volumetrics among PWH. To accomplish this, baseline sociodemographic, clinical, and substance use data as well as plasma samples from the RV254/SEARCH010 cohort, one of the largest cohorts of individuals undergoing extensive clinical phenotyping in Bangkok, Thailand from acute through chronic HIV, were leveraged. In paper 1, we characterized individuals within the cohort across machine learning derived depressive symptom trajectories. In paper 2, we attempt to understand the biological mechanisms underlying depressive symptom trajectories through targeted proteomic analyses. In paper 3, we attempt to understand if these biological mechanisms extend to the brain, and identify proteomic signatures associated with concurrent brain volumetrics. Together, these studies combine clinical, molecular and neuroimaging data to improve our understanding of biological processes linking AHI to long-term neuropsychiatric outcomes.