Neurotrophic Factor Signaling in the Pathogenesis of HIV-associated Depression: Cohort and Mechanistic Studies

Abstract Neurotrophic Factor Signaling in the Pathogenesis of HIV-associated Depression: Cohort and Mechanistic Studies Depression in people with HIV is known to worsen HIV outcomes as well as quality of life. Prior studies have shown Brain Derived Neurotrophic Factor (BDNF) is pivotal in neuron development and maintenance and important in depression. To better understand the pathophysiology of depression in HIV, we desire to use proteomics to further study the BDNF pathways in pre- existing CSF samples from people with HIV and then do a proof-of-concept test in a murine HIV model of depression. We have access to cerebrospinal fluid from a cohort of outpatients with HIV collected in a study of HIV-associated Neurocognitive Disorders with CSF and clinical data collection at 0 and 2 years. The evaluation included neurocognitive testing and depression screening with the center for epidemiological studies depression (CESD). We plan to do discovery and validation proteomics with focus in the validation proteomics for the BDNF pathway. We will use a machine-learning analysis plan comparing our proteomics findings with the CESD generally and on an item-level basis as well as cognitive evaluations using the NIMH Research Domain Criteria (RDoC) constructs with focus on Loss, Reward Valuation, and Cognition. We plan to do this analysis first cross-sectionally and then further validate by comparing longitudinally. We hypothesize CSF neurotrophic factor BDNF with neuroinflammatory markers are associated with depressive symptoms; strength of association with depressive symptoms will vary within RDoC domains with persistent neuroinflammation closely tied to ongoing symptoms. We plan to use our findings from proteomics in an HIV murine model of depression with focus on the BDNF pathways. We plan to acquire humanized mice and infect half with HIV. We will evaluate them for depression and then inject half with a BDNF antagonist and evaluate again with standard depression testing. We hypothesize the treated mice to exhibit more signs of depression than untreated mice (less sucrose preference, less social interaction, less immobile time) as BDNF improves resilience and neuroplasticity. Successful completion will yield impactful data on the BDNF pathways and could discover additional targets for treatment of HIV-associated depression.