# Immunometabolicgene expression profiles associated with depressed mood and behavioral domains inpeople with HIV

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $696,003

## Abstract

SUMMARY
This project will leverage emerging knowledge about the role of immunometabolism in the pathophysiology of
depression in people with HIV to generate hypotheses about potential future treatments. Depression in PWH
is characterized by features that differentiate it from depression in people without HIV (PWoH). The first is the
predominance of anhedonia - inability to gain enjoyment from activities. The second is a higher prevalence of
depression that is resistant to treatment with standard antidepressant drugs in PWH versus PWoH. These
clinical observations suggest not only that the underlying pathophysiology of depression is different between
the two populations, but that different treatments are needed to successfully treat depression in PWH.
Molecular studies of immunometabolism, defined as reciprocal interactions between immunity and metabolism
that are dysregulated and linked to depression in PWH, support these distinctions. Based on our preliminary
data and that in the literature, we propose to perform RNA-Seq transcriptomics, relating immunometabolic
gene expression to protein and other biomarkers of immunometabolism, and to clinical depression as well as
to cognitive processes impacted by depression. Our hypothesis-driven approach will focus on two interacting,
co-regulated gene pathways central to depression and immunometabolism, the mammalian target of
rapamycin (mTOR) and the NLRP3 inflammasome. We will study 80 newly recruited PWH and 40 age-
matched PWoH. Given our early work suggesting that the relationship between immunometabolism and
depression is sex-dependent, we aim for a 50/50 breakdown of men and premenopausal women in order to
examine sex differences in these relationships. To optimize the spectrum of depressive symptom severity in
our sample (e.g., avoid over-representation of individuals with minimal depressive symptoms), we will stratify
with a 50/50 breakdown above and below the previously established Beck Depression Inventory-II cut-score
for clinically-significant depressive symptoms (≥16). Since clinical studies cannot rigorously establish
mechanistic relationships, we will study in parallel the roles of mTOR and NLRP3 inflammasome signaling in
depression-like behaviors in a mouse model of HIV infection, EcoHIV, which expresses seven of nine key
human HIV proteins. These pathways will be dissected using mTOR and NLRP3 inhibitors. Also, in these
animals we will characterize immunometabolic markers in brain tissue, presumably the substrate of
depression.

## Key facts

- **NIH application ID:** 10487532
- **Project number:** 5R01MH128869-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** RONALD J. ELLIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $696,003
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487532

## Citation

> US National Institutes of Health, RePORTER application 10487532, Immunometabolicgene expression profiles associated with depressed mood and behavioral domains inpeople with HIV (5R01MH128869-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10487532. Licensed CC0.

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