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.

Grant Number: 5R36MH139364-02
NIH Institute/Center: NIH
Principal Investigator: Jennifer Chavez