Probing the Proteome: Depressive Symptoms, Inflammation and Mitochondrial Perturbations in Acute HIV Infection - PROJECT SUMMARY The primary objective of the proposed R36 is to elucidate molecular mechanisms whereby inflammation and mitochondrial dysfunction, both in the presence and absence of amphetamine-type stimulant use during acute HIV infection, can predict persistent depressive symptoms over 96 weeks of suppressive antiretroviral therapy. By 2030, it is expected that the two leading causes of disease around the world will be HIV and depressive disorders, and the excess burden among people with HIV (PWH) is estimated to be three times higher than among those without HIV. During AHI, gut immune dysfunction can lead to the release of proinflammatory cytokines into the periphery. These cytokines can cross the blood brain barrier, leading to damage in the brain and alterations of the functional connectivity of key circuits involved in emotional processes and the hypothalamic-pituitary-adrenal axis stress response associated with depressive symptoms. Several studies have also independently linked mitochondrial stress and depressive symptoms. When stressed, mitochondria activating potent inflammatory cascades, which contribute to the heightened inflammatory state that is often characteristic of AHI. Amphetamine-type stimulant use (ATS) is also known to increase HIV pathogenesis in the central nervous system, contribute to oxidative stress and increase serum biomarkers of inflammation. ATS can also lead to significant changes in the dopamine and glutaminergic systems, both of which are involved in substance use and depression. Taken together, these disturbances can increase oxidative stress and exacerbate neuroinflammation. Therefore, this study proposes to leverage the explanatory strength of proteomics to identify biological signatures underlying distinct trajectories of depression in PWH, by leveraging 100 plasma samples from the RV254/SEARCH010 cohort, the largest prospective investigation of individuals who have undergone extensive clinical phenotyping from acute through chronic HIV. Based on previous characterizations of depressive symptom trajectories over 96 weeks, Aim 1 will determine the associations of proteomic alterations relevant to inflammation and mitochondrial dysfunction of persistent [n=50] (versus resolved [n=50]) depressive symptoms over 96 weeks of suppressive ART. Aim 2 will examine if recent ATS use amplifies the associations of these proteomic alterations with persistent (versus resolved) depressive symptoms over 96 weeks of suppressive ART. Proteomic signatures will be identified using the SomaScan Assay, a highly multiplexed aptamer-based proteomic technology. The depth of the data that will be collected through this study will provide exceptional opportunities to further interrogate neuroimmune mechanisms relevant to persistent depressive symptoms and neurocognitive impairment in a planned K99/R00 proposal.
